Community-Acquired Respiratory Infections (Infectious Disease and Therapy)

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Community-Acquired Respiratory Infections Antimicrobial Management edited by

Charles H. Nightingale Hartford Hospital Hartford and University of Connecticut School of Pharmacy Storrs, Connecticut, U.S.A.

Paul G. Ambrose Cognigen Corporation Buflalo, New York, U.S.A.

Thomas M. File, Jr.

Northeastern Ohio Universities College of Medicine Rootstown and Summa Health System Akron, Ohio, U.S.A.

rn U.A L . ..R..C- E ..

D E K K E R

MARCEL DEKKER, INC.

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NEWYORK BASEL

Although great care has been taken to provide accurate and current information, neither the author(s) nor the publisher, nor anyone else associated with this publication, shall be liable for any loss, damage, or liability directly or indirectly caused or alleged to be caused by this book. The material contained herein is not intended to provide speciﬁc advice or recommendations for any speciﬁc situation. Trademark notice: Product or corporate names may be trademarks or registered trademarks and are used only for identiﬁcation and explanation without intent to infringe. Library of Congress Cataloging-in-Publication Data A catalog record for this book is available from the Library of Congress. ISBN: 0-8247-4698-8 This book is printed on acid-free paper. Headquarters Marcel Dekker, Inc., 270 Madison Avenue, New York, NY 10016, U.S.A. tel: 212-696-9000; fax: 212-685-4540 Distribution and Customer Service Marcel Dekker, Inc., Cimarron Road, Monticello, New York 12701, U.S.A. tel: 800-228-1160; fax: 845-796-1772 Eastern Hemisphere Distribution Marcel Dekker AG, Hutgasse 4, Postfach 812, CH-4001 Basel, Switzerland tel: 41-61-260-6300; fax: 41-61-260-6333 World Wide Web http://www.dekker.com The publisher oﬀers discounts on this book when ordered in bulk quantities. For more information, write to Special Sales/Professional Marketing at the headquarters address above. Copyright n 2003 by Marcel Dekker, Inc. All Rights Reserved. Neither this book nor any part may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, microﬁlming, and recording, or by any information storage and retrieval system, without permission in writing from the publisher. Current printing (last digit): 10 9

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PRINTED IN THE UNITED STATES OF AMERICA

INFECTIOUS DISEASE AND THERAPY Series Editor

Burke A. Cunha Winthrop-University Hospital Mineola, and State University of New York School of Medicine Stony Brook, New York

1. Parasitic Infections in the Compromised Host, edited by Peter D. Walzer and Robert M. Genta 2. Nucleic Acid and Monoclonal Antibody Probes: Applications in Diagnostic Methodology, edited by Bala Swaminathan and Gyan Prakash 3. Opportunistic Infections in Patients with the Acquired Immunodeficiency Syndrome, edited by Gifford Leoung and John Mills 4. Acyclovir Therapy for Herpesvirus Infections, edited by David A. Baker 5. The New Generation of Quinolones, edited by Clifford Siporin, Carl L. Heifetz, and John M. Domagala 6. Methicillin-Resistant Staphylococcus aureus: Clinical Management and LaboratoryAspects, edited by Mary T. Cafferkey 7. Hepatitis B Vaccines in Clinical Practice, edited by Ronald W. Ellis 8. The New Macrolides, Azalides, and Streptogramins: Pharmacology and Clinical Applications, edited by Harold C. Neu, Lowell/ S. Young, and Stephen H. Zinner 9. Antimicrobial Therapy in the Elderly Patient, edited by Thomas T. Yoshikawaand Dean C. Norman 10. Viral Infections of the Gastrointestinal Tract: Second Edition, Revised and Expanded, edited by Albert Z.Kapikian 11. Development and Clinical Uses of Haemophilus b Conjugate Vaccines, edited by Ronald W. Ellis and Dan M. Granoff 12. Pseudomonas aeruginosa Infections and Treatment, edited by Aldona L. Baltch and Raymond P. Smith 13. Herpesvirus Infections, edited by Ronald Glaser and James F. Jones 14. Chronic Fatigue Syndrome, edited by Stephen E. Straus 15. lmmunotherapy of Infections, edited by K. Noel Masihi 16. Diagnosis and Management of Bone Infections, edited by Luis E. Jauregui 17. Drug Transport in Antimicrobial and Anticancer Chemotherapy, edited by Nafsika H. Georgopapadakou

18. New Macrolides, Azalides, and Streptogramins in Clinical Pr4actice, edited by Harold C. Neu, Lowell S. Young, Stephen H. Zinner, and Jacques F. Acar 19. Novel Therapeutic Strategies in the Treatment of Sepsis, edited by David C. Morrison and John L. Ryan 20. Catheter-Related Infections, edited by Harald Seifed, Bernd Jansen, and Barry M. Farr 21. Expanding Indications for the New Macrolides, Azalides, and Streptogramins, edited by Stephen H. Zinner, Lowell S. Young, Jacques F. Acar, and Harold C. Neu 22. Infectious Diseases in Critical Care Medicine, edited by Burke A. Cunha 23. New Considerations for Macrolides, Azalides, Streptogramins, and Ketolides, edited by Stephen H. Zinner, Lowell S. Young, Jacques F. Acar, and Carmen Ortiz-Neu 24. Tickborne Infectious Diseases: Diagnosis and Management, edited by Burke A. Cunha 25. Protease Inhibitors in AIDS Therapy, edited by Richard C. Ogden and Charles W. Flexner 26. Laboratory Diagnosis of Bacterial Infections, edited by Nevi0 Cimolai 27. Chemokine Receptors and AIDS, edited by Thomas R. O’Brien 28. Antimicrobial Pharmacodynamics in Theory and Clinical Practice, edited by Charles H. Nightingale, Take0 Murakawa, and Paul (3.Ambrose 29. Pediatric Anaerobic Infections: Diagnosis and Management, Third Edition, Revised and Expanded, ltzhak Brook 30. Viral Infections and Treatment, edited by Helga Riibsamen-Waigmann, Karl Deres, Guy Hewleff, and Reinhold Welker 31. Commundy-Acquired Respiratory Infections: Antimicrobial Managiement, edited by Charles H. Nightingale, Paul G. Ambrose, and Thornas M. File, Jr.

Additional Volumes in Production

Preface

Even in this age of modern medicine, community-acquired respiratory tract infections continue to plague mankind. Most recently, with the outbreak of the severe acute respiratory syndrome (SARS) virus, we have seen the potential danger these infections pose in our increasingly global world. In this publication our objective is to address the current and emerging issues and problems facing the clinician in the treatment of communityacquired respiratory tract infections. One of these problems is the lack of rapid diagnostic tools, which may result in treatments that focus around empirical therapy. An issue of concern is the increased reporting of antibioticresistant organisms, indicating that some antimicrobial agents have limited utility. This in turn increases the pressure on the clinician to prescribe newer and newer medications. The question becomes how much of this is a real issue and how much involves the marketing strategies of drug manufacturers. Out of necessity, issues related to drug choice and doses and dosing regimens become important considerations. Concurrently, most modern approaches to dosage and dosage issues involve incorporating the pharmacodynamic properties of antibiotics into the decision-making process. In addition, the pressures of managed care to see as many patients as possible in the shortest period of time present real challenges for the practitioner. The book reviews each important community-acquired disease state and focuses on the objectives described above. The discussion of antibiotics is from two perspectives: clinical use and pharmacodynamics, for use in prescribing doses and dosing regimens based on the most recent information. iii

iv

Preface

Recognized experts in the pharmacology and pharmacodynamics of antibiotics have contributed chapters on speciﬁc classes of antibiotics. Specialists in infectious disease and experts in the treatment of communityacquired respiratory infections have written the clinical chapters. These chapters focus on clinical presentation, diagnostic modalities, and treatment. This book is a practical guide for the treatment of the most common community-associated respiratory infections. In addition to the medical aspects of the treatment of patients, the book provides the pharmacodynamic basis for some of the treatment drug choices, especially for the dose and dosing regimen. It incorporates the most recent data and combines it with proven clinical approaches. Antimicrobial recommendations from practice management guidelines have been included whenever appropriate. This material will be useful and practical for clinicians in the management of patients with community-acquired respiratory infections. This book is a collaborative eﬀort of pharmacologists, clinical pharmacists, and physicians that will be invaluable to all. In particular, it should be of interest and service to family practitioners, general internists, infectious disease specialists, pulmonologists, and pharmacists. Charles H. Nightingale Paul G. Ambrose Thomas M. File, Jr.

Contents

Preface Contributors

iii ix

Part One Overview 1. Overview of Community-Acquired Respiratory Tract Infections Thomas M. File, Jr. 2. Current Issues Involved in the Treatment of Community-Acquired Pneumonia Richard Quintiliani, Naomi R. Florea, and Charles H. Nightingale 3. Cost Considerations in the Use of Antibiotics for the Treatment of Community-Acquired Respiratory Tract Infections Joseph L. Kuti

1

31

43

Part Two Antibiotics and Their Usage in Community-Acquired Respiratory Tract Infections 4. The Role of Macrolides in the Treatment of Community-Acquired Pneumonia William R. Bishai and Charles H. Nightingale

59 v

vi

5. Treatment of Community-Acquired Respiratory Tract Infections with Ketolides Paul B. Iannini 6. Treatment of Community-Acquired Respiratory Tract Infections with Quinolone Antibacterial Agents Vincent T. Andriole, Paul G. Ambrose, and Robert C. Owens, Jr.

Contents

75

95

7. Treatment of Community-Acquired Respiratory Tract Infections with Penicillins and Cephalosporins Sandra L. Preston and George L. Drusano

121

8. Treatment of Community-Acquired Respiratory Tract Infections with Other Antibiotics William A. Craig and David R. Andes

145

Part Three Treatment of Commonly Encountered CommunityAcquired Respiratory Tract Infections 9. Acute Community-Acquired Rhinosinusitis James A. Hadley

155

10. Otitis Media Scott F. Dowell

181

11. Acute Pharyngitis James S. Tan and Blaise L. Congeni

201

12. Acute Exacerbations of Chronic Obstructive Pulmonary Disease Antonio Anzueto and Sandra G. Adams 13. Treatment of Pneumonia in Nonhospitalized Patients Thomas M. File, Jr. 14. Treatment of Hospitalized Patients with CommunityAcquired Pneumonia Michael S. Niederman 15. Anaerobic Pleuropulmonary Infection Matthew E. Levison

215 255

279 307

Contents

16. Treatment of the Common Cold and Viral Bronchitis Harley A. Rotbart 17. Treatment of Inﬂuenza-Related Respiratory Tract Infections Ann L. N. Chapman and Martin J. Wood

vii

321

341

18. Severe Acute Respiratory Syndrome Thomas M. File, Jr.

365

Index

375

Contributors

Sandra G. Adams, M.D. The University of Texas Health Science Center at San Antonio and The South Texas Veterans Health Care System, San Antonio, Texas, U.S.A. Paul G. Ambrose, Pharm.D. U.S.A. David R. Andes, M.D. U.S.A.

Cognigen Corporation, Buﬀalo, New York,

University of Wisconsin, Madison, Wisconsin,

Vincent T. Andriole, M.D. Haven, Connecticut, U.S.A.

Yale University School of Medicine, New

Antonio Anzueto, M.D. The University of Texas Health Science Center at San Antonio and The South Texas Veterans Health Care System, San Antonio, Texas, U.S.A. William R. Bishai, M.D., Ph.D. more, Maryland, U.S.A.

John Hopkins School of Medicine, Balti-

Ann L. N. Chapman, M.D., Ph.D. England

Royal Hallamshire Hospital, Sheﬃeld,

Blaise L. Congeni, M.D. Northeastern Ohio Universities College of Medicine, Rootstown, and Children’s Hospital Medical Center of Akron, Akron, Ohio, U.S.A. ix

x

Contributors

University of Wisconsin, Madison, Wisconsin,

William A. Craig, M.D. U.S.A.

Scott F. Dowell, M.D. U.S. Centers for Disease Control and Prevention and Thai Ministry of Public Health, Nonthaburi, Thailand George L. Drusano, M.D. U.S.A.

Albany Medical College, Albany, New York,

Thomas M. File Jr., M.D. Northeastern Ohio Universities College of Medicine, Rootstown, and Summa Health System, Akron, Ohio, U.S.A. Naomi R. Florea, Pharm.D. U.S.A. James A. Hadley, M.D. ter, New York, U.S.A.

Hartford Hospital, Hartford, Connecticut,

University of Rochester Medical Center, Roches-

Paul B. Iannini, M.D. Danbury Hospital, Danbury, and Yale University School of Medicine, New Haven, Connecticut, U.S.A. Joseph L. Kuti, Pharm. D. U.S.A.

Hartford Hospital, Hartford, Connecticut,

Matthew E. Levison, M.D. Drexel University College of Medicine, Medical College of Pennsylvania Hospital, Philadelphia, Pennsylvania, U.S.A. Robert C. Owens, Jr., Pharm.D. U.S.A.

Maine Medical Center, Portland, Maine,

Michael S. Niederman, M.D. Winthrop University Hospital, Mineola, and State University of New York at Stony Brook, Stony Brook, New York, U.S.A. Charles H. Nightingale, Ph.D. Hartford Hospital, Hartford, and University of Connecticut School of Pharmacy, Storrs, Connecticut, U.S.A. Sandra L. Preston, Pharm.D. U.S.A.

Albany Medical College, Albany, New York,

Richard Quintiliani, M.D. Hartford Hospital, Hartford, and University of Connecticut School of Medicine, Farmington, Connecticut, U.S.A.

Contributors

xi

Harley A. Rotbart, M.D. University of Colorado Health Science Center, Denver, Colorado, U.S.A. James S. Tan, M.D. Northeastern Ohio Universities College of Medicine, Rootstown, and Summa Health System, Akron, Ohio, U.S.A. Martin J. Wood, M.D.y

y Deceased.

Heartlands Hospital, Birmingham, England

1 Overview of Community-Acquired Respiratory Tract Infections Thomas M. File, Jr. Northeastern Ohio Universities College of Medicine, Rootstown and Summa Health System Akron, Ohio, U.S.A.

INTRODUCTION Community-acquired respiratory tract infections (CRTIs) are a leading cause of morbidity and mortality in the United States and worldwide, and they are associated with substantial health care costs. In addition, CRTIs are the most common reason for the use of antimicrobial agents, much of which use is inappropriate. In recent years, the management of these infections has been challenged by the escalation of antimicrobial resistance among predominant pathogens. Optimal treatment outcomes for CRTIs depend on appropriate and prompt initiation of antibiotic therapy when indicated. Appropriate therapy for these infections presents a signiﬁcant challenge to practicing clinicians in the light of rising time constraints and the increasing pressure for treatment to be cost-eﬀective. Ultimately, the best outcomes for patients depend on several factors, which include the establishment of an accurate diagnosis, the consideration of likely pathogens and their patterns of resistance, and the selection of an appropriate antibiotic based on eﬃcacy, pharmacology, and 1

2

File

tolerability. Promoting the appropriate use of antibiotics through the development and application of treatment guidelines and educational eﬀorts aimed at clinicians as well as patients should help curb unnecessary prescribing and misuse of antibiotics, decrease treatment costs, and increase patient satisfaction. This chapter is designed to provide an overview of the overall impact of CRTIs and to identify important diﬃculties in the diagnosis and treatment of patients suﬀering from such diseases. IMPACT OF CRTIs Morbidity and Mortality Community respiratory tract infections are the most common type of infection managed by health care providers and they are of great consequence [1,2]. Although many of these infections are of relatively mild severity, some may be associated with signiﬁcant morbidity or mortality. The widespread morbidity and mortality caused by CRTIs are serious problems for society. Acute respiratory tract infections are the greatest single cause of death in children worldwide (4.3 million deaths in 1992) [2]. Lower respiratory tract infections and inﬂuenza are responsible for most deaths caused by infectious disease in the United States. According to the National Center for Health Statistics (NCHS) of the Centers for Disease Control and Prevention, there were more than 200 million episodes of respiratory disorders (including infections and other conditions such as asthma) reported in the United States in 1996 [3]. During the years 1980 through 1996, respiratory tract infections (including upper respiratory tract infections, otitis, and lower respiratory tract infections) accounted for 16% of all outpatient visits to physicians [4]. The rate of visits for outpatient care ranged from 74/1000 population per year for lower respiratory tract infections and inﬂuenza to 200/1000 population per year for upper respiratory tract infection. The NCHS reported morbidity due to respiratory infections in 1996 led to 152 days lost from school per 100 youths, and 99 days lost from work per 100 employed persons [3]. In addition, recent indicators of overall burden of respiratory infections suggest that the morbidity and mortality rates attributed to some of these infections is increasing as well, in part because of the proportion of attributed hospitalizations [5]. Many factors, such as the emergence of acquired immune deﬁciency syndrome [AIDS] and increased antibiotic resistance, probably contribute to this increase. Upper CRTIs The most frequent CRTIs are acute upper respiratory tract viral respiratory infections (VRIs) which encompass a range of illnesses with the common cold

Overview of CRTIs

3

being most widespread. Children have an average of three to eight colds annually; incidence decreases with age to an average of about two to four colds a year by adulthood [6]. In 1996, data from a survey by the NCHS reported 62 million cases of colds required some form of treatment [7]. Gonzales et al. reported there were 25 million oﬃce visits to primary care providers in 1998 for upper respiratory tract infections, most of which were viral in etiology [8]. For otitis media and otitis externa, an average of 19,000 outpatient visits per year occurred from 1980 to 1996 [4]. For children younger than 15 years, acute otitis media was the most frequent diagnosis in physician’s oﬃce practice. This disease is less common in older children and adults; however, it can still be a signiﬁcant cause of illness in older patients as well. Sinusitis is one of the most common health care complaints among adults in the United States, with a minimum of 35 million cases diagnosed by physicians annually [9]. However, because many episodes are unreported, many patients suﬀer without seeking care from a physician. Lower RTIs The prevalence of chronic bronchitis and chronic obstructive pulmonary disease (COPD) is increasing worldwide. An estimated 20–30 million persons in the United States suﬀer from these conditions [10–13]. While for the past few years all the other leading causes of death in the United States, such as heart disease, stroke, and cancer, have been declining, the number of deaths due to COPD has actually increased over the same time period by 22% [14]. Much of the morbidity, mortality, and cost expended for COPD is associated with patients who present with diﬃcult-to-treat cases and/or multiple recurrences of infectious exacerbation. In the United States, approximately 4–5 million cases of communityacquired pneumonias (CAP) occur each year, accounting for 10 million physician visits, approximately 500,000 hospitalizations, and approximately 45,000 deaths [15]. Mortality has ranged from 2% to 30% among hospitalized patients; mortality is less than 1% for patients who are not hospitalized. CAP occurs more commonly in children under the age of 5 years and in adults over the age of 65 years. The incidence of CAP for persons between the ages of 5 and 60 years has been reported to be between 100 and 500 per 100,000 population [16]. In a series of studies, Foy and coworkers examined the incidence of pneumonia by age in a prepaid medical care group that had a population of 180,000 when the study ended in February 1975 [16]. The overall annual rate of pneumonia was 12 per 1,000 population per year. Rates were highest in the 0–4 years age group at 12 to 18 per 1,000 population. Between the ages of 5 and 60 years, the rate ranged from 1 to 5 per

Symptoms of the respiratory system (n = 24,851) Acute upper respiratory infections of multiple or unspecified sites (n = 13,874) Acute tonsillitis and acute pharyngitis (n = 13,706) Acute bronchitis (n = 10,852) Acute sinusitis (n = 9,856) 1,822

688

628

951 889

3,098

613

448

1,114 700

Inpatient Outpatient

674

682

350

455

883

449

441

315

356

602

88

114

72

81

157

335

474

156

297

776

429

443

211

301

507

Disability Absenteeism Prescription costs costs drug Office Othera

Health care costs

Costs per beneficiary, $

Overall costs

3,564

4,219

2,180

2,791

35,126,784

45,784,588

29,879,080

38,722,334

7,845 194,956,095

Total costs

Aggregate Employer Costs, $b

Employer Payments in 1997 per Beneﬁciary, by Type of Respiratory Infection, and Employer Overall Costs

Respiratory Infections

TABLE 1

4 File

1,200 1,168 886

1,902 787

1,038 1,047

990 2,054 498

6,316 940

1,315 1,459

680 598

973 455

409

820

787

437 413

604 449

371

518

516

112 97

242 95

75

168

102

621 437

1,016 252

179

668

404

525 346

491 301

224

478

456

46,591,584 6,692,439

11,793,888

31,108,704

32,824,440

4,728 7,158,192 4,397 280,924,330

11,544 3,279

2,642

5,874

4,455

Includes care at patient’s home, nursing/extended care facility, psychiatric day-care facility, substance abuse treatment facility, and independent clinical laboratories. b Aggregate employer costs is calculated by multiplying total costs by the number of beneficiaries with a specific condition. Source: Ref. 21.

a

Chronic sinusitis (n = 7,368) Chronic bronchitis (n = 5,296) Strep throat and scarlet fever, chronic pharyngitis and nasopharyngitis, chronic diseases of the tonsils and adenoids (n = 4,464) Pneumonia (n = 4,036) Acute nasopharyngitis (acute cold) and acute laryngitis (n = 2,041) Influenza (n = 1,514) Unique individuals in respiratory infections sample (n = 63,890)

Overview of CRTIs 5

6

File

1,000 population. In 1987, Houston et al. retrospectively evaluated the incidence of pneumonia (nursing home and community-associated) in elderly patients and residents 65 years of age or older in Homestead County, Minneapolis, Minnesota [17]. The overall incidence rate for an initial episode of pneumonia was 3,032 per 100,000 population; this rate rose to 7,923 per 100,000 population among residents aged 85 or older. In a prospective study of all adult patients (z18 years of age) hospitalized for CAP in two counties in Ohio during 1991 (Ohio Community Based Pneumonia Incidence Study) Marston et al. reported an incidence of 280 cases per 100,00 population [18]. The rate was 962 cases per 100,000 for persons older than 65 years of age. In this study, the incidence was higher among blacks than whites and higher among males than females. The incidence of CAP (like most CRTIs) is highest in the winter months and during inﬂuenza epidemics. The mortality of CAP has not changed signiﬁcantly over the past 2 decades in part due to the increased number of patents at risk for CAP (i.e., elderly patients and patients with multiple comorbid conditions). In a prospective study of prognostic factors of CAP due to bacteremic pneumococcal disease in ﬁve countries, mortality ranged from 6% in Canada to 20% in the United States and Spain (13% in the United Kingdom and 8% in Sweden) [19]. Independent predictors of death were age greater than 65, nursing home residence, presence of chronic lung disease, high APACHE score, and need for mechanical ventilation. Diﬀerences in disease severity and frequency of underlying conditions were factors for diﬀerent outcomes. In a subsequent study, Mortensen et al. found approximately half of the CAP deaths were due to worsening of preexisting conditions [20]. Cost of RTIs Patients with respiratory tract infections represent an important ﬁnancial burden on society. In one study, the estimated cost to employers of patients with respiratory tract infections in the United States in 1997 was $112 billion, including costs of medical treatment and time lost from work [21]. Patients with pneumonia, ‘‘symptoms of the respiratory system,’’ and chronic bronchitis averaged the highest costs at $11,544, $7,845, and $5,874 per employee, respectively (Table 1). Costs associated with the common cold have been estimated to exceed $3.5 billion per year in the US [6]. Sinusitis is also a substantial economic burden, associated with high health care costs and reduced quality of life. In a recent study, 26.7 million patient visits were attributed to sinusitis and related airway disorders, at a cost of $5.78 billion [22]. Cases in adults accounted for most of the overall costs.

Overview of CRTIs

7

The cost of treating CAP and acute exacerbations of chronic bronchitis (AECB) is also high. One study found that the total direct cost, in 1995 dollars, of treating pneumonia patients younger than 65 years of age in the United States was $3.6 billion per year and was $4.8 billion for patients 65 years or older [23]. Another study estimated the annual cost to employers for employees with pneumonia was ﬁve times higher than for employees without pneumonia [24]. In a recent estimate, the direct costs of COPD in the United States were $14.5 billion; much of this is due to the management of AECB [25]. The largest proportion of these costs, $7.8 billion, was related to hospitalization, with the second most signiﬁcant cost factor being drugs at $5.1 billion. Antibiotic costs made up 6.5% of these drug costs (approximately $330 million), and therefore only a small proportion of the total costs. GENERAL APPROACH TO ANTIMICROBIAL THERAPY OF CRTIs Respiratory tract infections are the reason for most antibiotic use. Approximately three-quarters of all outpatient antimicrobials used in the United States are for respiratory tract infections [26]. However, a large proportion of these prescriptions are unnecessary because many of the treated conditions (i.e., common cold, acute bronchitis, acute uncomplicated rhinosinusitis) have a predominantly viral etiology, and antibacterial therapy has not been shown to have a beneﬁcial impact. The Centers for Disease Control and Prevention estimates that approximately 59% of the approximately 100 million courses of antibiotics prescribed by oﬃce-based physicians are unnecessary [27]. The common colds and related VRI syndromes are among the most frequent reasons for inappropriate antibiotic use; this increases the costs of illness unnecessarily and contributes to the increasing prevalence of antibiotic-resistant pathogens. Thus, the progress previously made in dealing with the most common bacterial cause of respiratory tract infections, Streptococcus pneumoniae, is now associated with a global explosion of drug resistance that has made treatment decisions very diﬃcult. The appropriate management of CRTIs poses multiple challenges for the clinician. Prescribers are faced with an ever-increasing selection of antimicrobial agents from which to choose the most appropriate therapy for their patients (Table 2). The likelihood of achieving a successful outcome is inﬂuenced by a number of factors involving the patient, the pathogen, and the drug. A primary consideration is whether antimicrobial agents are warranted in the ﬁrst place. This involves diﬀerentiating viral from bacterial etiology to the best extent possible: such knowledge is critical in order to

8

File

TABLE 2 Commonly Used Antimicrobials for Community Respiratory Tract Infections (antibacterials and antivirals for infections associated with immunocompetent hosts) Antibacterials h-Lactams Penicillin VK Amoxicillin/Ampicillin Amoxicillin/clavulanate Ampicillin/sulbactam Oral cephalosporins (i.e., cefuroxime, loracarbef, ceprozil, cefpodoxime, ceftibutin, cefdinir) Parenteral cephalosporins (i.e., cefuroxime, cefotaxime, ceftriaxone) Macrolides Erythromycin, dirithromycin, clarithromycin, azithromycin Ketolides Telithromycin Clindamycin Tetracyclines Tetracycline, doxycycline Trimethoprim/sulfamethoxazole Fluoroquinolones Ofloxacin, ciprofloxacin, levofloxacin, sparfloxacin, gatifloxacin, moxifloxacin, gemifloxacin Others: Linezolid, vancomycin Antivirals Acyclovir, valacyclovir, famciclovir Amantadine, rimantadine, zanamavir, oseltamavir

determine whether patients require antibiotic therapy. Bacterial infections warrant antimicrobial therapy, whereas viral infections do not require antibiotics. Viral illness generally resolves within a week, whereas bacterial infections typically worsen and can be accompanied by clinical signs of infection. If antimicrobial agents are warranted, the clinician then must decide which of the many agents available is most appropriate for each individual patient. Many factors need to be considered, which include likely pathogens, severity of illness, patient age, safety proﬁle, concomitant medications, comorbidities, antimicrobial activity, pharmacokinetic/pharmacodynamic parameters, clinical experience, ease of administration, local epidemiological considerations, and concern for development of resistance (Table 3). Antibiotics, when used appropriately, are eﬀective in eradicating pathogens causing bacterial RTIs, leading to more rapid resolution of infection and improvement of symptoms. For example, in patients with acute com-

Overview of CRTIs

TABLE 3

9

Factors for Consideration of Antimicrobial Choice

for CRTIs Antimicrobial activity against most likely pathogens Epidemiological considerations: Age, comorbid conditions, travel, animal-exposure, etc. Safety profile (adverse effects and drug interactions) Pharmacokinetic/pharmacodynamic parameters Potential for resistance Cost

munity-acquired bacterial sinusitis, Gwaltney and coinvestigators showed that antibiotics improved symptoms and decreased or eradicated bacteria from the maxillary sinus [28]. Recovery also is more rapid in children with acute sinusitis who are treated with antimicrobials compared with those treated with placebo [29]. Antibiotics also can help avoid complications, such as in patients with bacterial acute otitis media (AOM). Treatment of bacterial AOM with an antibiotic that provides coverage for the most common pathogens can help avoid the potential consequences of untreated or incorrectly treated disease, including hearing impairment and delayed speech development [30]. Antibiotics also can help prevent the progression of disease from acute to chronic manifestations. The Challenge of Identifying the Causative Pathogens Myriad microorganisms can cause CRTIs, including bacteria and viruses. However, a handful of most likely microorganisms are responsible for the majority of infections (Table 4). Viruses such as rhinoviruses are undoubtedly responsible for the majority of mild CRTIs. The most frequent and clinically signiﬁcant bacterial pathogen associated with CRTIs is S. pneumoniae, which is the most common bacterial pathogen for CAP, otitis, and sinusitis and a common cause of AECB. Hemophilus inﬂuenzae is also an important cause of CAP, AECB, sinusitis, and otitis. The so-called atypical pathogens such as Mycoplasma, Legionella, and Chlamydia species are emerging as increasingly recognized causes of CAP and occasionally of AECB. Septococcus pyogenes and viruses are the most common microorganisms associated with tonsillitis/ pharyngitis. Gram-negative bacilli and Staphylococcus aureus may be the cause of CRTI in selected patients especially those with multiple comorbid conditions. Mycobacteria, fungi, and so forth may be associated with CRTIs (especially CAP), based on epidemiological considerations. At the time of patient presentation to the physician, the microbial etiology of the infection is generally unknown. No convincing association

10

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TABLE 4 Microbial Etiology of Common Community Respiratory Tract Infections (relative percentages) Pathogen S. pneumoniae H. influenzae S. pyogenes M. pneumoniae C. pneumoniae L. pneumophila S. aureus Gram negative Virus

Common cold

Pharyngitis

15–30 1

100%

35–40

Otitis media

Sinusitis

AECB

CAP

25–65 20–40 1–6

35 20–30 2–4

10–15 20–35

20–60 10

<10 <10

1–30 5–20 1–5 3–5 3–10 10–20

10–30

2–8 0–10 4–25

<10 <10 30

AECB = Acute exacerbations of chronic bronchitis. CAP = Community-acquired pneumonias.

has been demonstrated between individual symptoms, physical ﬁndings or laboratory test results, and speciﬁc etiology in most cases of CRTIs. While there may be epidemiological associations with a variety of speciﬁc pathogens, physicians cannot reliably predict the etiology based on the initial clinical manifestations. Furthermore, for most CRTIs there is at present no test that oﬀers a simple, rapid, cost-eﬀective, accurate means of identifying the causative pathogen at the initial point of service (i.e., clinicians’ oﬃce). With the exception of the rapid group A streptococcus test for pharyngitis, techniques to identify the causative pathogen are often insensitive or generally unavailable in most clinical settings. Subsequently, therapy is usually initiated empirically using antimicrobials with activity against the most likely causative pathogens. Challenge of Differentiating Viral from Bacterial RTI A signiﬁcant challenge to clinicians is to distinguish which patients with symptoms of a community respiratory infection warrant antimicrobial therapy. Often clinical ﬁndings are not deﬁnitive with this process. Establishing the correct diagnosis—whether viral or bacterial infection—is key to limiting the use of unnecessary antibacterial agents. It is estimated that as many as 50 million antibiotic prescriptions a year could be avoided if clinicians diﬀerentiated between viral and true bacterial RTIs [30,31]. However, for the clinician faced with a patient exhibiting cough, nasal congestion, postnasal drip, nasal discharge, or pressure or pain over the sinuses, diﬀerentiating viral from bacterial illness may present a challenge. Symptoms often

Overview of CRTIs

11

overlap, and it is acknowledged that bacterial infections may follow viral disease. Antibiotics do not eradicate viruses and do not shorten the course of viral illness. In fact, when antibiotics are given for viral infections, the result may be subsequent infection with resistant bacteria because previous antibiotic exposure may provide a selective advantage for resistant bacteria [32]. Furthermore, antibiotic use can aﬀect others, fostering the carriage of resistant organisms among children in day-care centers and to other family members [33,34]. As previously indicated, there is a lack of rapidly available, costeﬀective diagnostic tests that reliably diﬀerentiate self-limiting viral infection from bacterial infection. However, practice guidelines can oﬀer pragmatic criteria for better antimicrobial usage. Thus, although initially suﬀering from a viral infection, 60% of patients with symptoms of sinusitis persisting for 10 days have a bacterial infection [35]. Restriction of antibiotics to only those patients would signiﬁcantly reduce unnecessary prescribing. In addition, the restriction of antibiotic therapy in otitis media to those children with acute bacterial disease and avoidance in otitis media with eﬀusion could reduce unnecessary use by two-thirds [36]. Moreover, there is little evidence that antibiotic therapy inﬂuences the outcome of acute bronchitis or milder exacerbation of chronic bronchitis, and prescribing could again be dramatically reduced [37]. Thus, more precise discrimination of probable viral versus bacterial CRTIs could improve the quality of therapy. Although acute pharyngitis is most commonly viral in etiology, an important bacterial pathogens is S. pyogenes (group A streptococcus). It is therefore important to diﬀerentiate streptococcal from viral etiology in order to direct the most appropriate therapy. The concerns for complications of group A streptococcal infection (i.e., acute rheumatic fever and glomerulonephritis) are other reasons for appropriate diagnosis. The severity of illness due to S. pyogenes, as well as the presenting symptoms and signs, varies greatly. In most cases, diﬀerentiation of streptococcal etiology from viral etiology is not reliably accurate on clinical grounds alone. The presence of pharyngeal exudate and tender adenopathy may help in the diagnosis, but these ﬁndings are not speciﬁc or sensitive. The challenge for the clinician is to specify the etiology so that appropriate therapy can be administered. A variety of empirical approaches have been recommended but remain controversial. Guidelines by the Infectious Diseases Society of America and the Pediatric Red Book recommend cultures or antigen testing to allow the best utilization of antimicrobial agents [38,39]. For otitis media (OM), it is also important to diﬀerentiate between true acute otitis media (AOM) and otitis media with eﬀusion (OME), because OME does not warrant antibiotic use. AOM is diagnosed when ﬂuid is present in the middle ear and is accompanied by signs or symptoms of acute illness

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(e.g., ear pain, otorrhea, or fever). In contrast, clinical signs of infection do not accompany OME, which also involves ﬂuid in the middle ear. Several factors may help clinicians distinguish between viral and bacterial rhinosinusitis. For example, viral illness is usually self-limiting, lasting 2 to 7 days [40]. In contrast, bacterial infections typically worsen after a week or do not resolve after 7 to 10 days. Although a thick, discolored nasal discharge is often seen in patients with CRTIs, this sign is not a deﬁnitive indication that a bacterial infection is present. In these patients, it may be prudent to reserve antibiotics unless the condition persists beyond 7 to 10 days. Acute bacterial rhinosinusitis (ABRS) is usually preceded by a viral upper CRTI. Clinical judgment is used to distinguish between viral illness and ABRS. Some of the key clinical symptoms of viral and bacterial disease are listed in Table 5. AECB due to bacterial infection—which may account for up to 50% of AECB and warrants antibacterial therapy—is very diﬃcult to diﬀerentiate from exacerbation due to nonbacterial etiologies (i.e., viruses, pollutants, allergens). However, it is important that the clinician try to distinguish AECB from acute viral bronchitis, which does not require antimicrobial therapy. AECB is deﬁned as an illness in a patient with chronic bronchitis

TABLE 5

Symptoms Associated with Viral and Bacterial Rhinosinusitis

Viral illness (usually lasting 2–7 days) Sneezing Rhinorrhea Nasal congestion Hyposmia/anosmia Sore throat Postnasal drip Fever Cough Ear fullness Facial pressure

ABRS (persisting beyond 5–7 days) Purulent nasal drainage Fatigue Nasal congestion Hyposmia/anosmia Maxillary facial pain Postnasal drip Fever Cough Ear fullness/pressure Facial pain/pressure (especially unilateral and focused)

Myalgia Note: Worsening of symptoms after 7 days may indicate bacterial infection ABRS = acute bacterial rhinosinusitis. Source: Ref. 27.

Overview of CRTIs

13

(deﬁned as a productive cough for at least 3 months for 2 consecutive years), which is characterized by an increase in at least one of three cardinal symptoms: dyspnea, sputum volume, or sputum purulence [41,42]. Acute bronchitis is generally used to describe a transient (usually<15 days) respiratory illness that occurs among patients without chronic lung inﬂammatory conditions and is characterized by cough (with or without sputum, fever, or substernal discomfort) and in the absence of radiographic ﬁndings of pneumonia [43]. Timely and accurate diagnosis and treatment of AECB remain challenges to clinicians because of the indeﬁnite beginnings and uncertain treatment modalities of the condition. Because patients with AECB have chronic bronchitis as an underlying disease and because the deﬁnition of AECB is subjective, it is sometimes diﬃcult to determine when an exacerbation has begun or ended. The appropriateness of antimicrobial therapy in AECB is controversial, particularly in the light of current trends in resistance. However, because recurrent episodes of AECB can impair pulmonary function and can severely impact quality of life, many clinicians choose to treat the condition with antibiotics in order to address those cases that are bacterial in origin. To help decide whether antimicrobial therapy is warranted, clinicians are encouraged to stratify patients by the type of exacerbation and by the presence of risk factors associated with poor outcome. Randomized, placebo-controlled trials have shown that antibiotic treatment is beneﬁcial in selected patients with AECB [44]. Speciﬁcally, studies show that patients with more severe exacerbation (type I) are more likely to experience beneﬁt than those with less severe disease. Patients with type I exacerbation have all three cardinal symptoms: increased dyspnea, increased sputum volume, and increased sputum purulence; patients with type II exacerbation have two symptoms, and patients with type III have only one. In comparison, patients with moderate exacerbation (type II) experienced less beneﬁt from antibiotics compared with those who received placebo, and patients with mild episodes (type III) did not appear to beneﬁt from antibiotic treatment compared with the placebo group. In one study, patients with AECB who received antibiotic therapy had a more rapid return of peak ﬂow, were more likely to achieve clinical success, and experienced clinical failure less frequently than patients given placebo [44]. Other studies also have shown the beneﬁt of antibiotic therapy in AECB [45]. A clinical practice guideline for management of AECB formulated by the American College of Physicians–American Society of Internal Medicine and the American College of Chest Physicians was recently published; this position paper recommends the use of antibiotics in patients with severe exacerbation (such as type I) of COPD [46]. In addition to stratiﬁcation by type, high-risk patients for poor outcome of AECB have been identiﬁed: these include patients with a history of repeated infec-

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tions (>4 per year), comorbid illnesses (such as diabetes, asthma, coronary heart disease), or marked airway obstruction (<50% FEV1) [47]. In patients with AECB of bacterial origin, antibiotics may have a longterm beneﬁt of decreasing the amount of bacteria chronically colonizing the airway once the patient is clinically stable, thus helping to prevent progression to parenchymal lung infection [48]. Antibiotic treatment may also prevent progressive airway injury due to persistent infection and may prolong the duration between exacerbations. The challenge facing the clinician in establishing a diagnosis of CAP is to distinguish it from less serious respiratory infections such as acute bronchitis. Table 6 lists characteristics associated with both conditions [49– 51]. A deﬁnitive diagnosis of CAP cannot be based on clinical symptoms alone; a chest x-ray is necessary to determine the presence of pneumonia. Challenge of Resistance The discovery of potent antimicrobial agents was one of the greatest contributions to medicine in the 20th century. Unfortunately, the emergence of antimicrobial-resistant pathogens now threatens these advances. Over the past decade, antibiotic resistance has increased markedly among common respiratory pathogens, most notably in S. pneumoniae isolates, and, to a lesser extent, Haemophilus inﬂuenzae and Moraxella catarrhalis. Figure 1 illustrates the varying degrees of resistance to penicillin of S. pneumoniae over recent years. A parallel and equally troubling development has been the rise of crossresistance involving other h-lactam and non–h-lactam antibacterial agents as well (e.g., cephalosporins, macrolides, clindamycin, tetracycline, chloramphenicol, trimethoprim/sulfamethoxazole, and, to a lesser extent, ﬂuoroquinolones) [52]. TABLE 6

Characteristics of Acute Bronchitis and CAP

Acute Bronchitis Transient duration (<15 days) in patients without chronic lung disease Cough F sputum Substernal discomfort FFever >90% viral No chest x-ray evidence of pneumonia CAP = community-acquired pneumonia. Source: Ref. 49.

CAP Cough Sputum production Dyspnea Fever Altered breath sounds Rales Chest x-ray evidence of pneumonia

Overview of CRTIs

15

FIGURE 1 Emergence of penicillin-resistant S. pneumoniae in respiratory specimens. (From Refs. 52–58.)

Inappropriate use of antibiotics has contributed to the development of drug resistance among the most common bacterial pathogens in RTIs—S. pneumoniae, H. inﬂuenzae, and M. catarrhalis. The increase in resistance is a result of several factors, but a major factor driving resistance is the overall volume of antimicrobial prescribing—particularly for indications that do not warrant such therapy. Thus, it is vitally important that judicious use of antimicrobials be encouraged in order to curb this overuse and, it is hoped, minimize emergence of resistance. Among respiratory pathogens, drug-resistant S. pneumoniae (DRSP) is of the greatest concern because it is the dominant cause of CAP. Surveillance studies indicate that the prevalence of DRSP continues to increase worldwide [53–58]. In two recent multinational studies, the worldwide prevalence of penicillin-resistant and macrolide-resistant S. pneumoniae ranged from 17.7% to 22.3% and 26.4% to 31.8%, respectively [57,58]. The dominant factor in the emergence of DRSP in one U.S. study has been human-to-human spread of relatively few clonal groups that harbor resistance determinants to multiple classes of antibiotics (including cephalosporins, macrolides, doxycycline, trimethoprim/sulfamethoxazole) [59]. Despite the rapid increase in DRSP, the clinical relevance for the outcome of some CRTIs remains controversial depending on the class of antimicrobial agent considered. The impact of S. pneumoniae drug resistance on morbidity and mortality associated with meningitis is well documented, and mounting evidence suggests that such resistance may also explain the

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decreased clinical and bacteriological response rates now seen in otitis media as well [60]. The clinical relevance of penicillin-resistant S. pneumoniae appears to vary depending on the level of resistance and the site of infection. For CAP, intermediate resistance (MIC 0.1–1.0 Ag/mL) has not been shown to be associated with a detrimental outcome; however, this same level of resistance can be signiﬁcant for otitis [61]. Until recently, however, studies of patients with CAP had failed to establish an independent association between drug-resistant S. pneumoniae and clinical outcome. Most studies suggest that current levels of h-lactam resistance do not generally result in treatment failures for patients with CAP [61]. Based on established pharmacokinetic/pharmacodynamic principles, adequate serum and tissue levels should be achieved with parenteral h-lactams or oral amoxicillin to eﬀectively treat the majority of CAP due to DRSP. An analysis of nine controlled trials of a high-dose oral formulation of amoxicillin-clavulanate found a good clinical response for respiratory infections (mostly in outpatients) caused by S. pneumoniae with penicillin MICs up to 8 Ag/mL [62]. Although most studies have not demonstrated an adverse eﬀect of h-beta lactam resistance on the outcome of pneumococcal pneumonia, most clinicians remain concerned that increased morbidity and mortality will be seen as the proportion of resistant strains and their MICs increase. Moreover, in two controlled studies of pneumococcal bacteremia, one found an increased risk of mortality in patients with high-level resistance (penicillin MIC z 4 Ag/ml) and another showed an increased risk of suppurative complications for nonsusceptible infections [63,64]. Risk factors for penicillin-resistant S. pneumoniae have been identiﬁed (i.e., age< than 2 years or > 65 years, h-lactam therapy within 3 months, alcoholism, medical comorbidities, immunosuppressive illness or therapy, and exposure to a child in a day-care center), although it is not clear these are speciﬁc enough for individual patients to be clinically reliable [65]. The clinical relevance of macrolide-resistant S. pneumoniae (MRSP) may be dependent on the type of resistance expressed by a particular strain. The most common mechanisms of resistance include methylation of a ribosomal target encoded by erm gene and eﬄux of the macrolides by cell membrane protein transporter, encoded by mef gene [66]. S. pneumoniae strains with mef are resistant at a lower level (with MICs generally 1 to 16 Ag/ mL) than erm-resistant strains; and it is possible that such strains (particularly with MIC< 8 Ag/mL) may be inhibited if suﬃciently high levels of macrolide can be obtained within infected tissue (such as may occur with newer macrolides—clarithromycin or azithromycin) [67–71]. However, there is recent evidence that the MICs of these strains are increasing, and this may aﬀect the eﬃcacy of these macrolides [72]. The mef-resistant strains are usually susceptible to clindamycin. Most erm-resistant isolates have an MIC above 32 Ag/mL for erythromycin and are considered high-level resistant for

Overview of CRTIs

17

all macrolides and clindamycin. Until recently, reports treatment of failure in CAP treated with macrolides have been rare, particularly for patients at low risk for drug-resistant strains. However, since 2000, anecdotal reports and one controlled study have documented failures due to MRSP in patients treated with an oral macrolide who subsequently required admission to the hospital with S. pneumoniae bacteremia [73–76]. Currently mef-associated resistance predominates in North America. Erm-associated resistance predominates in Europe and is common in Japan. Although the worldwide prevalence of pneumococcal resistance to the newer ﬂuoroquinolones (levoﬂoxacin, gatiﬂoxacin, moxiﬂoxacin) remains low (less than 2%), in some countries resistance has increased markedly [77– 79]. The overall prevalence of ﬂuoroquinolone resistance (levoﬂoxacin >4 Ag/mL) in Hong Kong in 2000 had increased to 13.3% due to the dissemination of a ﬂuoroquinolone-resistant clone [78]. Treatment failures have already been reported mostly in patients who have previously been treated with ﬂuoroquinolones [80,81]. Risk factors for levoﬂoxacin resistance were identiﬁed as prior exposure to a ﬂuoroquinolone, nursing home residence, nosocomial infection, and COPD [82]. In the light of the emerging resistance of the pneumococcus to existing drugs, alternative agents need to be considered. Although glycopeptides (i.e., vancomycin, teicoplanin) are nearly certain to provide antibiotic coverage for DRSP, they are not active against other key respiratory pathogens (i.e., atypicals, H. inﬂuenzae) and there is a strong reason not to use these drugs until needed because of fear of emergence of other resistant organisms (i.e., VRE, VRSA). Other agents eﬀective against DRSP include quinupristin/ dalfopristin, linezolid, and the ketolides. The focus of therapy of quinupristin/dalfopristin and linezolid is more for nosocomial infections (and particularly for VRE or MRSA). The ketolides (telithromycin is the ﬁrst to be marketed) are a novel addition to the macrolide group of antibacterials and have in vitro eﬃcacy against key respiratory pathogens (including penicillinand erythromycin-resistant strains) [83]. Principles of Appropriate Antimicrobial Use Because of the increase in resistance it is increasingly important that recommendations for judicious use of antibiotics for RTI be encouraged. It is hoped that when sound principles are applied to select an appropriate empirical agent, the costs associated with incorrect prescribing and multiple courses of antibiotics can be avoided. Principles of appropriate therapy should be promoted and utilized by prescribing clinicians in order to result in the best outcomes for patients and reduce the emergence of antibiotic resistance. Several core principles of antibiotic therapy that should provide optimal beneﬁt for patients as well as minimize resistance are listed in Table 7 [84].

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TABLE 7 1. 2. 3. 4. 5. 6.

Principles of Appropriate Antimicrobial Use

Use antibacterial therapy only in those patients with bacterial infection. Utilize diagnostic and other measures to reduce prescribing. Therapy should maximally reduce or eradicate the bacterial load. Use antimicrobial agents with optimal pharmacodynamics to achieve eradication. Use locally relevant resistance data in the decision process. Antimicrobial acquisition cost may be insignificant compared with therapeutic failure.

Source: Ref. 84.

Reduction of Unnecessary Antimicrobials Because inappropriate prescribing is the major inﬂuence on developing resistance, antimicrobial therapy should be limited to infections in which bacteria are the predominant cause. This principle certainly seems self-evident, but it is one to which adherence seems very diﬃcult. The reasons for overprescribing antibiotics are multifactorial. Patients may consult clinicians, expecting an antibiotic to be prescribed for an acute respiratory infection for which the etiology is most likely viral; as a result, clinicians may feel pressured to write antibiotic prescriptions to satisfy patients and to maintain good doctor-patient relationships. Receiving an antibiotic reinforces the patients’ perception that antibiotics are warranted in similar situations. Thus, patients may continue to consult clinicians each time similar symptoms occur, expecting that antibiotics are again needed. Clinicians also may prescribe antibiotics as a rapid means of treating patients’ symptoms rather than taking the time to educate patients that antibiotics are not always necessary, especially if a viral infection is suspected. However, clinicians should recognize that patient satisfaction is not compromised by the absence of an antibiotic prescription, provided patients understand the reasons. Hamm et al. demonstrated that patient satisfaction was inﬂuenced by patient perceptions that the clinician spent enough time discussing the illness and by patient knowledge about the treatment choice [85]. Moreover, clinicians may prescribe antibiotics as part of a defensive approach to avoid the potential sequelae of not prescribing for patients with bacterial infection. Unfortunately, most patients and many clinicians view ‘‘unnecessary’’ antibiotic prescribing as at worst a neutral intervention (i.e., cannot harm, but may help). It is imperative patients understand this is not the case. In fact, the unnecessary use of antibacterials has several possible harmful eﬀects in addition to selection of resistance, such as increased cost and exposure to

Overview of CRTIs

19

unnecessary adverse reactions. Decreasing excess antibiotic use is an important strategy for combating the increase in community-acquired antibioticresistant infections. Several studies have documented a beneﬁt of combining physician intervention and patient education that has resulted in decreased use of antimicrobials and reduction of resistance [86–88]. Additional Principles of Appropriate Antimicrobial Usage Antibiotics that maximize bacterial eradication improve both short and longer term clinical outcomes, reduce overall costs—particularly those relating to treatment failure and consequent hospital admission—and assist in the minimization of resistance emergence and dissemination. There is accumulating evidence to indicate bacterial eradication as the primary goal of antibiotic therapy and the main determinate of therapeutic outcome [89]. However, spontaneous clinical recovery, common in mild to moderate CRTIs, may mask diﬀerences in bacterial eﬀectiveness of antibiotics and allow suboptimal agents to continue to be prescribed. Thus, agents with poor bacteriological eﬃcacy can appear clinically almost as good as those with optimal eﬃcacy: the ‘‘Pollyanna eﬀect’’ [90]. These small diﬀerences, which may seem insigniﬁcant in small series, may translate to signiﬁcant numbers of failures in larger populations treated with suboptimal therapy. Antibiotic therapy that allows bacterial persistence risks not only poorer clinical outcome but also resistance selection. Pharmacodynamic (PD) properties can diﬀerentiate between antibiotic classes, often between members of the same class, in their ability to eradicate pathogens at drug concentrations attainable during therapy. Integration of minimum inhibitory concentrations (MIC) with pharmacokinetic (PK) parameters provides pharmacodynamic (PD) indices, which are valuable tools with which to predict clinical and bacterial outcomes. Antimicrobial therapy is intended to provide a concentration of the agent that exceeds the concentration needed to inhibit the infecting organism. Traditionally, the MIC, which deﬁnes the minimum amount of an antimicrobial necessary to inhibit the growth of a microbe, has been used to describe the in vitro activity of an agent against a speciﬁc organism. Microorganisms are identiﬁed as susceptible, intermediate, or resistant on the basis of speciﬁc MIC levels. These levels, or breakpoints, are generally determined by reference to levels of the drug achieved in human serum, rather than the concentration of the drug attained at the infection site. These breakpoint values may not correlate with recent clinical data. In contrast, pharmacodynamic breakpoints are based on the pharmacokinetic evaluation of antibiotic concentrations (usually using serum concentrations because they are readily measured) as well as the consideration for how diﬀerent antimicrobials exert their antibacterial action (i.e., time-dependent or concentration dependent killing), and corre-

20

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lated with clinical data on bacteriologic cure. Antibiotics that exhibit timedependent pharmacodynamic eﬀects are clinically successful when the serum concentration exceeds the MIC for 40% to 50% of the dosing interval [91]. For the h-lactams and the macrolides, clarithromycin and erythromycin, eﬃcacy depends on the amount of time the serum drug concentration exceeds the MIC of the agent. In contrast, the eﬃcacy of the ﬂuoroquinolones is concentration-dependent, with the pharmacodynamic breakpoint dependent on the ratio of the total concentration of the agent to the MIC of the agent against the pathogen. The PK/PD breakpoints primarily rely on the drug concentration achieved in serum that correlates well for infections such as otitis. For pneumonia, the pharmacokinetics of agents in the endothelial lining ﬂuid may be an appropriate marker of clinical eﬀect. However, as of yet clinical trial data have not yet supported or disproved this hypothesis. Strategies of appropriate empirical therapy should take into account the relative risks for drug-resistant strains. For example, whenever a prescription is written for a CRTI, the prescriber should inquire about factors associated with increased risk of DRSP—recent antimicrobial therapy (within 3 months), recent hospitalization (within 30 days) and whether or not a child who attends a day-care center resides within the household. If there is increased risk for DRSP, it is certainly appropriate to choose empirical therapy with agents likely to be eﬀective against such pathogens (i.e., new ﬂuoroquinolones, ketolides, or high-dose amoxicillin-containing agents). Acquisition costs of diﬀerent antimicrobials may be insigniﬁcant compared with the cost associated with therapeutic failure or adverse eﬀects. Drug acquisition costs are a primary consideration only if there are no signiﬁcant diﬀerences in treatment outcomes between agents; potential for selection of resistance; and incidence of signiﬁcant treatment-related adverse events. Thus, a more expensive agent may be much more cost-eﬀective if it is associated with greater eﬃcacy or better tolerance than a less expensive generic comparator. Alternately, a shorter course of equal eﬃcacy may minimize cost. If shorter courses result in similar results, they are clearly preferable. Inappropriate therapy of CRTI is expensive. In a study of LRTI, more eﬀective antimicrobial therapy cost an average of US $8821 per episode compared with US $14754 when treatment was less eﬀective [92]. Treatment failure far exceeds the acquisition costs of any antibiotic; and hospitalization is the key cost-driver. Thus, antibiotics that reduce the risk of hospitalization or reduce the length of stay in the hospital will be more cost-eﬀective; and agents that achieve improved bacterial eradication also have the potential to improve long-term clinical outcomes and reduce overall costs and, perhaps, limit resistance emergence and dissemination.

Overview of CRTIs

21

The Value of Guidelines The use of clinical practice guidelines can be an eﬀective means of changing behavior, such as promoting the appropriate use of antibiotics [93]. Eﬀective clinical guidelines should improve patient care while enhancing cost savings. However, cost savings should not be the primary motivating factor. For example, a recent report described a government intervention intended to decrease costs by reducing the use of ‘‘more-expensive,’’ second-line antimicrobials [94]. As a result, costs increased through the occurrence of adverse outcomes in patients with OM, sinusitis, lower RTI, and AECB. To maximize eﬀectiveness and applicability, antibiotic use guidelines should be evidence-based. The guidelines should also reﬂect data on resistance, recognizing that local patterns of resistance often diﬀer across geographic regions. Hence, eﬀective guidelines should be readily adaptable for implementation locally. Primary objectives of guidelines for treating CRTIs should be to discourage antibiotic use to treat viral illness, to outline diagnostic criteria, and to avoid the use of ineﬀective antimicrobials. Unfortunately, a meta-analysis of relevant studies has shown that there are numerous barriers to adherence to practice guidelines (Table 8) [95]. For example, clinicians may not be aware of all of the available guidelines or may not be well versed in how to apply speciﬁc recommendations appropriately. In addition, clinicians may not agree with some or all of the recommendations made or, as a general principle, may resist the concept of guidelines. If clinicians are doubtful that they can perform the task called for in the guidelines or harbor a belief that the recommendations will be unsuccessful, they probably will not follow the guidelines. Time constraints or health care organization requirements may impose restrictions that hamper the clinician’s ability to implement the guidelines. Furthermore, the clinician may not have control over some changes called for in guidelines, such as the acquisition of new resources to perform diagnostic tests. Patient preferences for alternatives not recommended in guidelines also may obstruct adherence to clinical practice guidelines. To be successful, educational eﬀorts and interventions aimed at improving adherence to practice guidelines—such as use of checklists and reminder systems—should address all of the identiﬁed barriers. Educational Strategies to Promote Rational Antibiotic Use Issuing guidelines on appropriate antibiotic use for treatment of diﬀerent types of infections is only the ﬁrst step in ensuring that rational principles are adopted and followed in clinical practice. Educational strategies aimed at enhancing clinician awareness of guidelines and encouraging their implementation is necessary. Educational materials promoting the implementation of

22

TABLE 8

File Barriers to Clinician Adherence to Clinical Practice Guidelines

Barrier Lack of awareness Lack of familiarity Lack of agreement

Lack of self-efficacy Lack of outcome expectancy Lack of motivation Guideline-related barriers Patient-related barriers Environmental-related barriers

Explanation Clinician unaware that the guidelines exist Clinician aware of guidelines but unfamiliar with specifics Clinician does not agree with a specific recommendation made in guideline or is averse to the concept of guidelines in general Clinician doubts whether he/she can perform the behavior Clinician believes the recommendations will be unsuccessful Clinician is unable/unmotivated to change previous practices Guidelines are not easy or convenient to use Clinician may be unable to reconcile guidelines with patient preferences Clinician may not have control over some changes (e.g., time, resources, organizational constraints)

Source: Ref. 95.

practice guidelines and emphasizing their beneﬁts could be developed and provided to clinicians. Translation of guidelines into practice also must involve educational eﬀorts geared toward patients. Patients need to understand that antibiotics are not appropriate for the treatment of viral infections. They also must be educated about the need to take antibiotics as directed and for the entire duration prescribed. Public health campaigns can help to spread the word, and traditional print and audiovisual patient education materials also may be useful. Educational eﬀorts aimed at providers and patients already have proved successful in promoting the rational use of antibiotics in community-acquired upper RTIs. In a study in rural Alaska, the education of health care workers and the community concerning appropriate antimicrobial use in children with community-acquired upper RTIs was associated with a 22% reduction in the number of antibiotic prescriptions in children younger than 5 years and with a 28% decrease in penicillin-resistant pneumococcal nasopharyngeal isolates compared with the two control regions not provided with the educational intervention [96].

Overview of CRTIs

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In addition to educational campaigns, there is no substitute for the few moments taken by the treating clinician to explain fully why antibiotics are not necessary or why they are being prescribed. This approach helps patients realize that their condition is being taken seriously. The investment in time and personal attention can increase patient satisfaction with the selected treatment and can help ensure that patients comply with therapy. CRTIs PREVENTION Measures to reduce the prevalence of bacterial CRTIs by the use of preventive vaccines are very relevant to the appropriate use of antimicrobials. Pneumococcal and inﬂuenza vaccines should reduce the incidence of bacterial infections (secondary infections in the case of inﬂuenza vaccine) and thereby reduce the use of antibiotics. Preliminary data indicate dramatic reductions in hospitalization and mortality from use of these vaccines, suggesting an associated reduced necessity of antimicrobial prescribing [97]. Despite controversies over eﬃcacy of the polysaccharide pneumococcal vaccine (PPV), both PPV and the inﬂuenza vaccines are recommended according to current guidelines by the Centers for Disease Control and Prevention (at ages 65 and 50, respectively, for immunocompetent adults without other risk factors) [98,99]. In a recent meta-analysis of 14 trials totaling more than 48,000 patients, PPV prevented deﬁnite pneumonia by 71% and mortality by 32% (but not all-cause death) [100]. However, there was no beneﬁt seen for patients aged 55 years or more. A signiﬁcant advance has been the development and licensure of the pneumococcal conjugate vaccine in infants. The beneﬁts of this vaccine over the PPV have yet to be demonstrated in adults. In addition to preventive vaccines, smoking cessation should also reduce the burden of CRTIs, and it is worth the eﬀort to provide counseling. CONCLUSIONS Community respiratory tract infections are the most common reason for antimicrobial usage. However, much of this use is inappropriate. It is, therefore, a signiﬁcant challenge for the practicing physician to distinguish which CRTIs warrant antibiotics. The challenge to use antibiotics for CRTIs appropriately is great because of the large number of potential respiratory pathogens, the large number of drugs available, and the increasing resistance of the former to the latter. A working knowledge of the antimicrobial and pharmacologic properties as well as the safety proﬁle of the available agents will provide the clinician a sound basis on which to make decisions regarding the use of antimicrobials for CRTIs. Antibiotic therapy with the appropriate agent shortens the course of the illness, lowers the risk of complications due

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to untreated disease, helps to prevent disease progression and airway impairment, and avoids the added cost of multiple courses of antibiotics.

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18. Marston BJ, Plouﬀe JF, File TM Jr, et al. Incidence of community-acquired pneumonia requiring hospitalization: results of a population-based active surveillance study in Ohio. Arch Intern Med 1997; 157:1709–1718. 19. Kalin M, Ortvist A, Almela M, et al. Prospective study of prognostic factors in community-acquired bacteremic pneumococcal disease in 5 countries. J Inf Dis 2000; 182:840–847. 20. Mortensen EM, Coley CM, Singer DE, et al. Arch Intern Med 2002; 162:1059– 1064. 21. Birnbaum HG, Morley M, Greenberg PE, Colice GL. Economic burden of respiratory infections in an employed population. Chest 2002; 122:603–611. 22. Ray NF, Baranjuk JN, Thamer M, et al. Healthcare expenditures for sinusitis in 1996. Contributions of asthma, rhinitis, and other airway disorders. J Allergy Clin Immunol 1999; 103:408–414. 23. Neiderman MS, McCombs JS, Unger AN, et al. The cost of treating community-acquired respiratory infection. Clin Ther 1998; 21:576–591. 24. Birnbaum H, Morley M, Greenberg P, et al. Economic burden of pneumonia in an employed population. Arch Intern Med 2001; 161:2725–2731. 25. Niederman MS, McCombs JS, Unger AN, Kumar A, Popovian R. Treatment costs of acute exacerbation of chronic bronchitis. Clin Ther 1999; 21:576–591. 26. McCaig LF, Hughes JM. Trends in antimicrobial drug prescribing among oﬃce-based physicians in the United States. JAMA 1995; 273:214–219. 27. File TM Jr, Hadley JA. Rational use of antibiotics to treat respiratory tract infections. Am J Manag Care 2002; 8:713–727. 28. Gwaltney JM Jr, Scheld WM, Sande MA, Sydnor A. The microbial etiology and antimicrobial therapy of adults with acute community-acquired sinusitis: a ﬁfteen-year experience at the University of Virginia and review of other selected studies. J Allergy Clin Immunol 1992; 90:457–462. 29. Wald ER, Chiponis D, Ledesma-Medina J. Comparative eﬀectiveness of amoxicillin and amoxicillin-clavulanate potassium in acute paranasal sinus infections in children: a double-blind, placebo-controlled trial. Pediatrics 1986; 77:795– 800. 30. Bluestone CD, Klein JO. Otitis media in infants and children. 2d ed. Philadelphia, PA: WB Saunders Co, 1995:145–240. 31. Dowell SF, Schwartz B, Phillips WR, and The Pediatric URI Consensus Team. Appropriate use of antibiotics for URIs in children, part II: Cough, pharyngitis and the common cold. Am Fam Physician 1998; 58:1335–1342. 32. Dowell SF, Schwartz B. Resistant pneumococci: protecting patients through judicious use of antibiotics. Am Fam Physician 1997; 55:1647–1654. 33. Mainous AG III, Evans ME, Hueston WJ, Titlow WB, McCown LJ. Patterns of antibiotic-resistant Streptococcus pneumoniae in children in a day-care setting. J Fam Pract 1998; 46:142–146. 34. Cherian T, Steinhoﬀ MC, Harrison LH, Rohn D, McDougal LK, Dick J. A cluster of invasive pneumococcal disease in young children in child care. JAMA 1994; 271:695–697. 35. Gwaltney JM Jr, Scheld WM, Sande MA, Sydnor A. The microbial etiology and antimicrobial therapy of adults with acute community-acquired sinusitis: a

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2 Current Issues Involved in the Treatment of Community-Acquired Pneumonia Richard Quintiliani Hartford Hospital, Hartford and University of Connecticut School of Medicine Farmington, Connecticut, U.S.A.

Naomi R. Florea Hartford Hospital, Hartford Connecticut, U.S.A.

Charles H. Nightingale Hartford Hospital, Hartford and University of Connecticut School of Pharmacy Storrs, Connecticut, U.S.A.

INTRODUCTION Community-acquired pneumonia is a common and serious illness, with an estimated 5.6 million cases a year in the United States. Of these, approximately 1.1 million patients require hospitalization [1,2]. Communityacquired pneumonia ranks sixth among the leading causes of death in the United States and ﬁrst among causes of death from an infectious disease, with 50,000 to 60,000 deaths attributed to the infection each year [1,2]. The 31

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mortality rate among outpatients with community-acquired pneumonia is low (<1–5%), but increases to 8–12% among those requiring hospitalization, and to 40% among those patients in the intensive care unit [3,4]. Moreover, the economic cost of community-acquired respiratory tract infections is high, with approximately 150 million workdays lost each year and medical costs exceeding $10 billion annually [5]. Of growing concern is the increase in resistance to traditionally potent antimicrobials among common organisms associated with communityacquired pneumonia. Ubiquitous organisms such as Streptococcus pneumoniae are becoming widely resistant to penicillins, cephalosporins, macrolides, tetracyclines, and trimethoprim/sulfamethoxazole. Resistance is even more of an issue with pathogens responsible for chronic care– and hospital-acquired pneumonia, such as Psuedomonas aeruginosa, Acinetobacter baumannii, Klebsiella pneumoniae, and Enterobacter cloacae. As a result, lower respiratory tract infections now often require treatment with expanded-spectrum antimicrobial agents. As a result of this ‘‘arms race’’ between bacteria and antibiotics, the need for optimal treatment strategies, as well as the use of newer antibiotics such as the antipneumococcal ﬂuoroquinolones, to treat respiratory tract infections is becoming increasingly urgent. This chapter reviews the current issues, guidelines, and pharmacodynamic optimization of antimicrobials in the treatment of community acquired respiratory tract infections.

COMMUNITY-ACQUIRED PNEUMONIA Community-acquired pneumonia (CAP) remains one of the more serious medical problems, being associated with considerable morbidity and mortality. It is estimated that 5.6 million American adults suﬀer from CAP each year, imposing a signiﬁcant economic burden on society, with annual expenditures approaching $10 billion [1,2,5]. Although diagnostic techniques and antibiotic therapies have improved, the optimal management of this disease remains controversial. Over the past decade, four principal guidelines have been published in North America by the following societies: the Infectious Diseases Society of America (IDSA) [6], the Centers for Disease Control and Prevention (CDC) [5], the American Thoracic Society (ATS) [7], and the Canadian Infectious Disease Society and the Canadian Thoracic Society [8]. The Canadian guideline recommendations are in agreement with those from the IDSA guideline except that it focuses on Canadian regional characteristics. Therefore, only the IDSA, CDC, and ATS will be discussed in this chapter, with an emphasis on empiric antibiotic management.

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GENERAL CONCEPTS FOR THE UNDERSTANDING OF THE GUIDELINES FOR THE TREATMENT OF COMMUNITY-ACQUIRED PNEUMONIA To understand the guidelines, one must be familiar with four important observations. First, the best outcomes in this infection occur with antibiotic regimens that provide reliable coverage against both the usual ‘‘typical’’ extracellular bacterial pathogens (e.g., Haemophilus inﬂuenzae, Streptococcus pneumoniae, Moraxella catarrhalis) and the ‘‘atypical’’ intracellular pathogens (e.g., Chlamydia pneumoniae, Mycoplasma pneumoniae, Legionella pneumophila). Although it was customary in the past to almost ignore the role of the atypicals, it is now recognized that at least 30% of serious pneumonia, especially in patients with various comorbidities, are caused by these organisms [9,10]. Furthermore, when a patient is ﬁrst seen, it is basically impossible to determine whether the responsible pathogen belongs to the typical or atypical group. Unfortunately, there is too much overlap in the x-ray, physical, and laboratory ﬁndings to make this separation. This observation has had a major impact on the guidelines because neither penicillins (e.g., amoxacillin, ampicillin/sulbactam, piperacillin/tazobactam) nor cephalosporins (e.g., ceftriaxone, cefotaxime, cefuroxime) penetrate inside cells and, hence, do not exhibit activity against the intracellular organisms. As a result, to obtain coverage for the atypical pathogens, another antibiotic, like a macrolide, that displays both activity against these organisms and good intracellular penetration has to be combined with these h-lactam agents. As will be discussed later, this has become the basis for the recommendation to use a combination of a h-lactam antibiotic and a macrolide for the treatment of CAP. Second, it has been shown that there is a signiﬁcant increase in morbidity and mortality if appropriate therapy is not initiated within 8 hours of the diagnosis, particularly in the elderly patient with multiple medical comorbidities [7]. This observation negates much of the value of sputum cultures, because the growth of bacteria typically requires more than 48 hr. Moreover, even the Gram stain of sputum may not be helpful unless it is performed on an adequate specimen that has been stained and interpreted properly. The use of guidelines to determine initial empiric therapy not only provides coverage for the possibility of a mixed bacterial and intracellular pathogen infection, but also provides for appropriate recommendations in a timely manner. Finally, once easily cured with old narrow-spectrum antibiotics, lower respiratory tract infection now often requires treatment with expandedspectrum agents, mainly due to the emergence of antibiotic-resistant strains of bacteria. Even ubiquitous organisms involved in CAP, such as S. pneumoniae, are becoming widely resistant to penicillins (f40%), cephalosporins,

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macrolides, tetracyclines, and trimethoprim/sulfamethoxazole [11]. Interestingly, this resistance is usually not a signiﬁcant problem in otherwise healthy patients but may be one in those with comorbid conditions, such as chronic pulmonary, cardiac, or renal disease, or in the elderly. Antimicrobial agents such as the antipneumococcal ﬂuoroquinolones, the ketolides, vancomycin, and linezolid maintain activity against drug-resistant S. pneumoniae (DRSP) and are viable treatment modalities in these circumstances.

CENTERS FOR DISEASE CONTROL AND PREVENTION (CDC) GUIDELINE The CDC guideline (Fig. 1) was based on the draft of a meeting held in March 1998 that convened the Drug-Resistant Streptococcus pneumoniae Therapeutic Working Group (DRSP-TWG) [5]. For the outpatient management of CAP, the CDC guidelines strongly recommend monotherapy with a macrolide (clarithromycin or azithromycin) or doxycycline. For children under age ﬁve, an oral h-lactam (cefuroxime axetil, amoxicillin, or amoxicillin-clavulanate) alone is recommended for outpatient empiric treatment because atypical pneumonia is extremely uncommon in this age group and doxycycline and ﬂuoroquinolones should be avoided. For non–intensive care unit–hospitalized patients, combination therapy with a parenteral h-lactam (cefuroxime, cefotaxime, ceftriaxone, or ampicillin/sulbactam) plus a macrolide (clarithromycin or azithromycin) is recom-

FIGURE 1 Guidelines for community-acquired pneumonia by CDC.

Current Issues in the Treatment of CAP

35

mended. For intubated or intensive care patients, the clinician has two suggested choices: combination intravenous therapy of a h-lactam antibiotic (ceftriaxone, cefotaxime, piperacillin/tazobactam) plus an intravenous macrolide or monotherapy with an antipneumococcal ﬂuoroquinolone.

INFECTIOUS DISEASES SOCIETY OF AMERICA (IDSA) GUIDELINE The IDSA guideline is summarized in Fig. 2 [6]. Like the CDC, the IDSA society also supports the use of monotherapy with macrolides or doxycycline for outpatients with CAP. However, they also recommend the use of antipneumococcal ﬂuoroquinolone as a therapeutic option for outpatients, especially those with multiple comorbidities. Furthermore, although the IDSA guideline still supports the use of combination therapy with a third-generation cephalosporin or a h-lactamase inhibitor and a macrolide, it mainly recommends monotherapy with the use of antipneumococcal ﬂuoroquinolones as ﬁrst-line drug therapy for the hospitalized patient.

AMERICAN THORACIC SOCIETY (ATS) GUIDELINE The ATS guidelines [7] (Fig. 3) are based on four patient stratiﬁcation groups. Patients are stratiﬁed according to their need for hospitalization, underlying cardiopulmonary disease, and risk factors for DRSP, enteric gram-negative organisms, or P. aeruginosa. Risk factors for DRSP include age older than 65 years, h-lactam therapy within the past 3 months, immune-suppressive illness (including treatment with corticosteroids), multiple medical comorbidities, and exposure to a child in a day-care center. Those at risk for infection with an enteric gram-negative organism include nursing home residents, those with

FIGURE 2 Guidelines for community-acquired pneumonia by IDSA.

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FIGURE 3 Guidelines for community-acquired pneumonia by ATS.

underlying cardiopulmonary disease, recent antibiotic therapy, and those with other medical comorbidities. Finally, patients at risk for infection with P. aeruginosa include those with structural lung disease, patients on corticosteroid therapy (>10 mg prednisone/day), use of broad-spectrum antibiotics for more than 7 days in the past month, malnutrition, and undiagnosed HIV infection [12–14]. Group one consists of outpatients that do not have cardiopulmonary disease and/or risk factors for DRSP or gram-negative organisms. Treatment of these patients is limited to an advanced-generation macrolide such as azithromycin or clarithromycin, with doxycycline as an alternative in those patients that are allergic to or intolerant of macrolides. Group 2 consists of outpatients that have cardiopulmonary disease and/or risk factors for DRSP or gram-negative organisms. Recommended therapy for these patients is an oral h-lactam (oral cefpodoxime, cefuroxime, high-dose amoxicillin, amoxicillin/clavulanic acid, or I.V. ceftriaxone followed by oral cefpodoxime) plus a macrolide or doxycycline. As with the IDSA guideline, the ATS guideline also recommends that an antipneumococcal ﬂuoroquinolone can be used in these patients as monotherapy. Patients in Group 3 are those requiring hospitalization. The guidelines suggest that in those patients with no risk factors, a macrolide or an antipneumococcal ﬂuoroquinolone used as monotherapy would suﬃce. However, in those patients with underlying risk factors, the addition of an intravenous h-lactam (cefotaxime, ceftriaxone, ampicillin/sulbactam, high-dose ampicillin) plus a macrolide or doxycycline should be employed. Once again, the use of a respiratory ﬂuo-

Current Issues in the Treatment of CAP

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roquinolone as monotherapy is recommended in these patients. Finally, group 4 consists of those patients that require admission to an intensive care unit. Treatment of these patients includes intravenous h-lactam therapy (cefotaxime, ceftriaxone) plus either intravenous azithromycin or an intravenous antipneumococcal ﬂuoroquinolone. Patients in the ICU that have risk factors for P. aeruginosa should receive an intravenous antipseudomonal h-lactam (cefepime, imipenem, meropenem, piperacillin/tazobactam) plus an antipseudomonal ﬂuoroquinolone (ciproﬂoxacin) or an antipseudomonal h-lactam plus an aminoglycoside plus either azithromycin or an antipneumococcal ﬂuoroquinolone.

INCREASING POPULARITY OF THE FLUOROQUINOLONES IN THE TREATMENT OF RESPIRATORY TRACT INFECTIONS A look at the current guidelines highlights the growing popularity of monotherapy with the antipneumococcal or third-generation ﬂuoroquinolones, such as levoﬂoxacin, gatiﬂoxacin, and moxiﬂoxacin. This popularity is due in most part to their almost uniform activity against the entire target organisms causing CAP, the ability to give them once-a-day, and their high degree of oral absorption (>90%), whereby allowing many patients to be treated without injectable antibiotics. These antimicrobials have suﬃcient pharmacokinetic properties to ensure delivery of active drug to the bacteria and thus are agents that are believed to be very eﬀective in bacterial eradication. Since they are very active and have good pharmacokinetics, the probability of selecting or stimulating the emergence of resistant bacteria is considered to be low. This is one of the major reasons for their current popularity. Another is the reported resistance of S. pneumoniae to the macrolides. Most of these reports come from isolates collected in hospitalized patients and may not have relevance to the treatment of patients in the community. In addition the reports of resistance are based on breakpoints, which may or may not be set properly. Unfortunately the perception (not the reality) of clinically relevant resistance causes many physicians to use a quinolone in place of a macrolide.

PHARMACODYNAMIC CONCEPTS A discussion of guidelines and optimal treatment modalities for CAP would not be complete without a brief focus on pharmacodynamic principles. In the past, dosing methods for antibiotics have been more a matter of style or habit than science. Recently, signiﬁcant information has emerged from animal models, in vitro pharmacodynamic experiments, volunteer studies and clinical outcomes studies that now allow us to administer antibiotics in an optimal

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way. This means administering the antibiotic to attain the best clinical response, the least amount of toxicity, the lowest cost, and the lowest chance for the emergence of bacterial resistance. The relationship between bacterial killing and microbiological activity is described by the area under the serum concentration-time curve (AUC) and minimum inhibitory concentration (MIC) of the antibiotic for the target organism(s) (i.e., the AUC:MIC ratio). Under certain conditions, the AUC can be simpliﬁed to either concentration or time of antibiotic exposure dependent activity against microorganisms. h-Lactams, glycopeptides, clindamycin, and macrolide agents kill bacteria in a similar, time-dependent fashion, in which the time that the drug concentration exceeds the MIC (time > MIC) at the site of the infection drives the killing of the infecting microbes [15]. The time above MIC pharmacodynamic parameter can therefore be used to predict the eﬃcacy of these drugs. Aminoglycosides (e.g., tobramycin, gentamicin, amikacin), ﬂuoroquinolones (e.g., ciproﬂoxacin, oﬂoxacin, levoﬂoxacin, gatiﬂoxacin), and amphotericin B eliminate microorganisms most rapidly when their concentrations are appreciably above the MIC of the targeted microorganism(s); hence, their type of killing is referred to as concentration-dependent or dosedependent killing [17]. In animal models of infection, including neutropenic animals, many more animals survive a potentially lethal challenge of bacteria if aminoglycosides are given as a single daily dose than if the same dose is divided on a q8h basis [16]. In humans it has been shown that aminoglycosides eradicate organisms best when they achieve levels that are approximately 10 to 12 times above the microorganism’s MIC [17]. Although ﬂuoroquinolones also exhibit concentration-dependent killing, excessively high concentrations (>10 Ag/mL) of these agents in serum can be associated with seizures and other potentially serious central nervous system (CNS) adverse reactions. When targeted against very sensitive organisms, a serum peak to MIC ratio of 10:1 can be obtained. For more moderately sensitive (or moderately resistant organisms), this ratio often cannot be reached without producing excessive toxicity. The goal in this situation is still, however, to maximize concentration-dependent killing for as long as possible without moving into toxic serum levels. Because the AUC is a measurement of both serum concentration and time of exposure of the organism to the antibiotic, the AUC:MIC relationship becomes the best predictor of the clinical response. Predictions from animal models of sepsis, in vitro pharmacodynamic experiments, and clinical outcomes studies indicate that the magnitude of the 24-hour AUC:MIC ratio can be utilized to predict clinical response. For instance, a 24-hour AUC:MIC ratio of 125 or greater has been associated with the best cure rates in the treatment of infections

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caused by gram-negative hospital-acquired aerobic enteric pathogens [18]. For gram-positive bacteria, like S. pneumoniae, it appears that the AUC:MIC ratio can be appreciably lower. Clinical failures or superinfections have not been associated with the respiratory ﬂuoroquinolones when the AUC:MIC ratio for this bacterium is consistently 30 or greater [19]. Achieving AUC: MIC ratios greater than 30–40 against S. pneumoniae, however, has not been associated with better clinical responses or less likelihood of the emergence of bacterial resistance. Regardless of the antibiotic chosen, the dose and dosing regimen must be such that a rapid response to the antibiotic is achieved. Unfortunately, most clinical trials do not report response rates as a function of time. Rather they use a somewhat arbitrary time called the test of cure (TOC). This is one time point where the patients are evaluated and the antibiotic is compared to the results of treating similar patients with the ‘‘gold standard.’’ Unfortunately, this does not compare the speed of response of the patient to either drug regimen, and important information is lost. TRANSITIONAL ANTIBIOTIC THERAPY Clinical stability in CAP, as assessed by improvements in signs and symptoms as well as laboratory values, can usually be seen within the ﬁrst 24–72 hours [7]. It is at this point that conversion from intravenous to oral therapy (I.V. to P.O.) should be initiated. In 1987, we introduced the term antibiotic ‘‘streamlining’’ to refer to the process of converting patients from complicated, often expensive, intravenous therapy to equally eﬃcacious, simple, and less expensive regimens [20]. When the conversion is from I.V. to P.O., the process is now often designated sequential, transitional, step-down, or switch therapy. The ﬂuoroquinolones have gained considerable attention as excellent transitional choices because of their high degree of bioavailability, exceeding 90%. There are many advantages to employing oral antibiotic therapy in the treatment of infections. Signiﬁcant cost reductions result from the conversion from I.V. to P.O. therapy because of lower drug acquisition costs, a reduction in pharmacy time in the preparation and mixing of drugs, the ability to deliver a drug without the intervention of intravenous technicians, and a reduction in the length of hospital stay. Investigators at Hartford Hospital found that pharmacist-initiated I.V. to P.O. conversion programs of levoﬂoxacin maximized the number of conversion candidates, led to a reduced length of stay, and resulted in a total provider savings of approximately $3,000 per eligible patient [21]. Perhaps the most important beneﬁt derived from oral antibiotic therapy is the removal of intravenous catheters, which are the major source of

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nosocomial bacteremia, especially that caused by staphylococci. It has been established that there are more than 20 million vascular catheters inserted annually in patients admitted to hospitals in the United States, resulting in more than 50,000 episodes of bacteremia or line sepsis [22]. The frequency of these infections is directly correlated with the duration of catheter insertion [23]. In a recent cost analysis of 104 patients with line sepsis, it was noted that the average additional cost from each episode of line sepsis was $3,707, and even higher ($6,064) if it was caused by Staphylococcus aureus. A number of these episodes, particularly those due to staphylococci, were associated with signiﬁcant morbidity and occasionally with mortality [24]. Criteria required for converting patients to oral therapy varies from hospital to hospital. The ATS guidelines recommend that patients should be switched to oral therapy if they meet four conditions: improvement in cough and dyspnea, afebrile (<100jF) on two occasions 8 hr apart, decreasing white blood cell count, and functioning gastrointestinal tract with adequate oral intake [7]. These guidelines can aid in formulating a set of criteria for one’s individual institution in order to yield the beneﬁts of conversion therapy. CONCLUSIONS At the present time, there are two popular ways to treat community-acquired pneumonia: one is to use monotherapy with a respiratory quinolone, doxycycline, or a macrolide, and the other approach is to employ the combination of a cephalosporin or h-lactamase inhibitor with a macrolide. Monotherapy with a macrolide or doxycycline is used for the otherwise healthy young adult, whereas monotherapy with a ﬂuoroquinolone or combination therapy is usually given to older patients, those with comorbidities, or both. When administering antimicrobial therapy, it is of great importance that the pharmacodynamic parameters of each agent be optimized in order to achieve optimal concentrations for the deﬁned dosing period. Finally, intravenous to oral conversion should be considered in order to reduce the length of hospitalization, risk of line sepsis, and additional labor and supply costs. REFERENCES 1. Garibaldi RA. Epidemiology of community-acquired respiratory tract infections in adults: incidence, etiology, and impact. Am J Med 1985; 78:32S–37S. 2. Niederman MS, McCombs JI, Unger AN, et al. The cost of treating community-acquired pneumonia. Clin Ther. 1998; 20:820–837. 3. Marrie TJ, Durant H, Yates L. Community-acquired pneumonia requiring hospitalization: a 5 year prospective study. Rev Infect Dis 1989; 11:586–599. 4. Woodhead MA, MacFarlane JT, McCracken JS, et al. Prospective study of

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6.

7.

8. 9.

10.

11.

12.

13.

14. 15.

16. 17.

18.

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the aetiology and outcome of pneumonia in the community. Lancet 1987; I:671–674. Heﬀelﬁnger JD, Dowell SF, Jorgensen JH, et al. Management of communityacquired pneumonia in the era of pneumococcal resistance. Arch Intern Med 2000; 160:1399–1408. Bartlett JG, Dowell SF, Mandell LA, File TM Jr, Musher DM, Fine MJ. Practice guidelines for the management of community-acquired pneumonia in adults. Clin Infect Dis 2000; 31:347–382. Niederman MS, Mandell LA, Anzueto A, et al. American Thoracic Society guidelines for the management of adults with community-acquired pneumonia: diagnosis, assessment of severity, antimicrobial therapy, and prevention. Am J Respir Crit Care Med 2001; 163:1730–1754. Mandell LA, Marrie TJ, Grossman RF, Chow AW, Hyland RH, the Canadian Community-Acquired Pneumonia Working Group. CID 2000; 31:383–421. Marston BJ, Plouﬀe JF, File TM Jr, et al. Incidence of community-acquired pneumonia requiring hospitalization: results of a population-based active surveillance study in Ohio. The Community-Based Pneumonia Incidence Study Group. Arch Intern Med 1997; 157:1709–1718. Lieberman D, Schlaeﬀer F, Boldur I, et al. Multiple pathogens in adult patients admitted with community-acquired pneumonia: a one year prospective study of 346 consecutive patients. Thorax 1996; 51:179–184. Doern GV, Pfaller MA, Kugler K, Freeman J, Jones RN. Prevalence of antimicrobial resistance among respiratory tract isolates of Streptococcus pneumoniae in North America: 1997 results from the SENTRY antimicrobial Surveillance Program. Clin Infect Dis 1998; 27:764–770. Ruiz M, Ewig S, Torres A, et al. Etiology of community-acquired pneumonia: impact of age, comorbidity, and severity. Am J Respir Crit Care Med 1999; 160:397–405. Rello J, Rodriguez R, Jubert P, Alvarez B. Severe community-acquired pneumonia in the elderly: epidemiology and prognosis. Clin Infect Dis 1996; 23:723– 728. Porath A, Schlaeﬀer F, Lieberman D. The epidemiology of community acquired pneumonia among hospitalized adults. J Infect 1997; 34:41–48. Craig WA. Interrelationship between pharmacokinetics and pharmacodynamics in determining dosage regimens for broad-spectrum cephalosporins. Diagn Microbiol Infect Dis 1995; 22:89–96. Dudley MN. Pharmacodynamics and pharmacokinetics of antibiotics with special reference to ﬂuoroquinolones. Am J Med 1991; Suppl 6A:45S–50S. Moore RD, Lietman PS, Smith CR. Clinical response to aminoglycoside therapy: Importance of the ratio of peak concentration to minimal inhibitory concentration. J Infect Dis 1987; 155:93–99. Schentag JJ, Nix DE, Adelman MH. Mathematical examination of dual individualization principles. I Relationships between AUC above MIC and area under the inhibitory curve for cefmenoxime, ciproﬂoxacin, and tobramycin. DICP Ann Pharmacother 1991; 25:1050–1057.

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19. Quintiliani R, Nicolau DP, Nightingale CH. Pharmacokinetic and pharmacodynamic principles in antibiotic usage. In: Johnson J, Yu V, eds. Infectious Disease and Antimicrobial Therapy of the Ears, Nose and Throat. chap 5. Philadelphia, Pa: W.B. Saunders Co, 1997:48–55. 20. Quintilani R, Cooper BW, Briceland LL, et al. Economic impact of streamlining antibiotic administration. Am J Med 1987; 82(4A):391–394. 21. Kuti JL, Le TN, Nightingale CH, Nicolau DP, Quintiliani R. Pharmacoeconomics of a pharmacist-managed program for automatically converting levoﬂoxacin route from i.v. to oral. Am J Health Syst Pharm 2002; 59:2209–2215. 22. Maki DG. Infection due to infusion therapy. In: Bennett JV, Brachman PA, eds. Hospital Infection. Boston, Mass: Little, Brown, 1986:561–580. 23. Read I, Body GP. Infectious complications of indwelling vascular catheters. Clin Infect Dis 1992; 15:197–210. 24. Arnow PM, Quimosing EM, Beach M. Consequences of intravascular catheter sepsis. Clin Infect Dis 1993; 16:778–784.

3 Cost Considerations in the Use of Antibiotics for the Treatment of Community-Acquired Respiratory Tract Infections Joseph L. Kuti Hartford Hospital Hartford, Connecticut, U.S.A.

INTRODUCTION Community-acquired respiratory tract infections (CRTIs) are among the most prevalent and serious infections in the United States, accounting for over 50 million physician visits, 5 million hospitalizations, and 100 thousand deaths annually [1–3]. As a result, the economic impact of CRTIs is substantial. In 1985, the cost of treating CRTIs was estimated to be over $15 billion (US, 1985) [4]. Not only are these costs signiﬁcantly greater today due to inﬂation as well as more costly treatment options, they also tend to be considerably underestimated because of the intrinsic error introduced in cost-of-illness studies. Moreover, the implications of increasing resistance among commonly encountered bacterial pathogens, which in turn may lead to clinical failure when inappropriate therapy is initiated empirically, will signiﬁcantly add to the total economic burden of CRTIs [5]. Infections of the lower respiratory tract, including community-acquired pneumonia (CAP) and acute exacerbations of chronic bronchitis (AECB), 43

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account for the majority of hospitalizations and deaths associated with CRTIs. CAP is the sixth leading cause of death in the United States, causing approximately 1.1 million hospitalizations and 45,000 deaths annually [3]. Furthermore, inpatient management of CAP, estimated at $7.5 billion (US, 1995) annually, accounts for over 90% of total treatment-associated costs. As mentioned in separate chapters in this book, Streptococcus pneumoniae is the predominant bacterial pathogen in the etiology of CAP; furthermore, resistance to commonly used antimicrobials in the community and hospital make appropriate empiric therapy vital to clinical as well as economic outcomes. Penicillin-nonsusceptibility in S. pneumoniae has been shown to increase hospital length-of-stay (LOS), thereby adversely aﬀecting hospital room, nursing, and pharmacy costs [6,7]. AECB, a component of chronic obstructive pulmonary disease, accounts for approximately 280,000 hospitalizations and $1.6 billion in total costs. Similar to CAP, costs due to hospitalizations accounted for the majority of expenses at approximately $1.5 billion [2]. S. pneumoniae, along with Haemophilus inﬂuenzae and Moraxella catarrhalis, are the predominant pathogens in AECB. Likewise, antimicrobial resistance among these pathogens can greatly aﬀect clinical and economic outcomes [8,9]. Conversely, upper respiratory tract infections such as sinusitis, pharyngitis, and acute otitis media (AOM), although associated with less mortality and hospitalization, occur more frequently in the community population and thus also incur signiﬁcant health care resource consumption and cost. AOM, for example, is the most commonly diagnosed bacterial infection in children and costs an estimated $5 billion annually [10]. Unlike CAP and AECB, the majority of these costs are incurred by prescription costs, physician oﬃce visits, and indirect costs, speciﬁcally work time lost by the caregiver [11]. It is obvious that the improper treatment of CRTIs can have devastating outcomes on health care costs. Consequently, health care reform and technological advances are creating changes in how health care interventions are evaluated. In the past decade, cost containment has at times appeared to overshadow clinical assessments; however, the goal of understanding both the costs and consequences of interventions is ultimately being acknowledged. Clinical endpoints are still necessary, of course, but are no longer suﬃcient to make fully informed patient care decisions. Nor is it appropriate to make a decision based primarily on cost. In other words, the cheapest antibacterial is not always the most cost-eﬀective, especially when the costs associated with resistance, treatment failures, and adverse events are considered. The purpose of this chapter is to highlight potential methods for reducing health care costs associated with the antibacterial treatment of CRTIs. Because hospitalization and treatment failure–associated costs appear to be most sig-

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niﬁcant, the greater part of this discussion will focus on these concerns. Examples of cost-beneﬁcial approaches to managing such infections in the institution will be provided. METHODS OF REDUCING ANTIMICROBIAL COST IN THE HEALTH CARE SETTING There are numerous methods described in the literature for reducing costs when treating patients with CRTIs. These include administering appropriate empiric antibacterial therapy based on pharmacodynamic principles (as covered in other chapters in this book) and providing therapy that encourages good patient compliance such as combination versus monotherapy, single daily dosing, and shorter treatment courses. Patient compliance to appropriate antibacterial therapy is cost-beneﬁcial by reducing treatment failures and readmissions and delaying the emergence of resistance. Finally, promoting intravenous to oral transitional therapy may reduce hospital LOS and avoid costly intravenous complications. None of these methods, however, will be successful if not actually put into practice; therefore, guidelines or clinical pathways can be instituted to lead health care practitioners down the most eﬃcient and cost-eﬀective treatment path for a speciﬁc health care setting. PATIENT COMPLIANCE Combination Versus Monotherapy Quintiliani and colleagues were the ﬁrst to introduce the concept of antibiotic streamlining, which included, initially, transitioning antibiotic courses from combination to monotherapy [12,13]. This concept was tested by Briceland and colleagues when an infectious diseases physician and clinical pharmacist rounded on all patients who had received at least 3 days of parenteral combination antimicrobial therapy [14]. Streamlining recommendations were made in 54% of these patients, accepted in 82%, and resulted in an average cost savings of $138.51 (US, 1988) per patient. The majority of the recommendations suggested discontinuing the current combination therapy and substituting a diﬀerent single agent, usually a broad-spectrum h-lactam. Monotherapy was more expensive in only 13 cases, usually when two inexpensive agents were replaced by a more costly single agent, such as converting from a gentamicin/cefazolin combination to ceftriaxone or cefotaxime. The increase in cost in these 13 cases was mainly due to the higher acquisition cost of the newer agent. However, comparisons of acquisition costs alone can be misleading if the two agents are not otherwise identical [15]. All costs incurred directly and indirectly by therapy must be considered in order to select the

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most cost-eﬀective medication. These include drug costs, administration costs (labor and supplies), costs incurred by treatment failures, costs created by drug-induced side eﬀects, drug interactions, and so forth [16]. Richerson and colleagues performed an economic evaluation of alternative antibiotic regimens in hospitalized patients with community-acquired pneumonia [17]. A decision-tree model was used to compare all associated costs from treatment of CAP with azithromycin, levoﬂoxacin, or a combination of cefuroxime plus erythromycin. Probabilities for obtaining clinical success and adverse reactions were taken from the literature and added to the tree at all decision nodes, as denoted by a circle (Fig. 1). The costs for each arm were derived from actual Hartford Hospital costs (US, 1998) and included

FIGURE 1 Decision tree analysis for alternative treatments of community-acquired pneumonia. ADE = adverse drug event.

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47

expenses associated with drug acquisition, supplies, drug-related adverse events, discontinuation rates requiring alternative therapy, and treatment failure. After performing several analyses to determine the eﬀect of signiﬁcant component costs on the decision outcome, the authors found that when drug acquisition costs alone were considered, levoﬂoxacin was the most expensive agent ($126), followed by the combination of cefuroxime/erythromycin ($83), and ﬁnally azithromycin ($80). However, as the authors added in other indirect costs, levoﬂoxacin became the most cost-eﬀective therapy ($208, 95% CI: 206–210), followed by azithromycin ($228, 95% CI: 224–232), and the combination regimen ($323, 95% CI: 320–326). Not until the eﬀectiveness of levoﬂoxacin was held below 70% did the decision change to favor azithromycin therapy; furthermore, under all reasonable estimates of eﬀectiveness, the levoﬂoxacin regimen was more cost-eﬀective than the combination regimen. Interestingly, this simulation may have actually underestimated the cost-eﬀectiveness of levoﬂoxacin therapy compared to other standards because the signiﬁcant cost of hospital LOS was not included in the analysis. Due to its large economic impact, the ability to save even one day of hospitalization could sway the decision in any treatment direction. Using data from a large clinical trial of patients with CAP, Dresser and colleagues performed a cost-eﬀectiveness analysis of another ﬂuoroquinolone antibiotic, gatiﬂoxacin, in comparison with the combination of ceftriaxone plus intravenous erythromycin [18]. Oral transitional therapy was encouraged after at least 2 days of intravenous therapy, and when clinically appropriate, patients could be converted to oral gatiﬂoxacin or oral clarithromycin as per their randomized grouping. Costs were broken up into level 1, 2, and 3 costs. Level 1 costs considers only the acquisition price of the study medication. Gatiﬂoxacin level 1 costs were signiﬁcantly lower than the combination therapy by an average of $51 (US, 2000), P < 0.0005. Level 2 costs, which include all costs directly related to antibiotic use and infection treatment, excluding hospital per diem, were also signiﬁcantly lower for gatiﬂoxacin by an average of $94 (US, 2000), P < 0.0005. Finally, level 3 includes all hospital costs; on this level, gatiﬂoxacin cost an average of $5,109 (US, 2000) per treatment course as compared with the combination therapy, which cost $6,164 (US, 2000), a diﬀerence of $1055 (US, 2000) in favor of the ﬂuoroquinolone, P = 0.0114. The diﬀerence was primarily due to a slightly lower hospital LOS with the gatiﬂoxacin regimen, 4.2 days versus 4.9. By including hospital LOS in the economic analysis, the diﬀerence in costs between these regimens was 21 times greater than if only acquisition pricing were considered. Furthermore, after performing sensitivity analysis by varying acquisition prices, hospital costs, and success rates, the economic decision could not be altered and remained in favor of once-daily monotherapy with gatiﬂoxacin.

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Once-Daily Dosing and Short-Duration Therapy A survey of patients receiving antibiotics demonstrated that short-course therapy, once-daily dosing, good eﬃcacy, and few side eﬀects were the most important characteristics of an antibiotic regimen [19]. Administering antimicrobials with a long half-life that allows for once-daily dosing, especially during outpatient treatment, can also further reduce costs [20]. In most cases, total treatment acquisition costs will be similar between newer once-daily antimicrobials compared with older drugs that require more frequent dosing. However, this relationship can vary in either direction depending on the length of treatment and the availability of generic products, which signiﬁcantly reduce cost. For example, penicillin VK administered at 250 mg four times a day for 10 days would cost an institution approximately $4.80 (US, 1997). Meanwhile, an azithromycin Z-PakR, which lasts 5 days, would cost $36.24 (US, 1997) [21]. Although the penicillin must be administered four times a day and given for twice as long, it is one-seventh the price of the ZPakR. Of course, when failure rates and adverse reactions are considered, the economic decision might favor the azithromycin therapy. Part of that failure rate involves patient compliance with the prescribed medication. Studies have demonstrated improved compliance leading to improved outcomes with once daily dosing versus multiple doses [22,23]. Older, yet cheaper antimicrobials that require administration three to four times a day do not coincide with the increasingly busy schedules of today’s lifestyle. What good is the cheaper agent if the patient does not take all the doses? More important, poor compliance to antibiotic therapy can lead to clinical failure, hospital readmission, and the emergence of bacterial resistance. For this reason, many older antibiotics have been remanufactured in extended-release formulations that allow for increased dosing intervals. Such is the case with clarithromycin, which is now available in an ER formulation enabling once-daily dosing. Table 1 displays a list of intravenous and oral antimicrobial agents that can be dosed once daily in the treatment of CRTIs. Shorter courses of antibacterial therapy will also increase patient compliance, potentially leading to increased success rates, lower resistance rates, and lower costs. The optimal duration of therapy for many CRTIs is controversial. Only recently have clinical trials evaluated the clinical response rates, and more important, relapse rates of antimicrobials when administered for shorter durations. A 5-day course of telithromycin, the ﬁrst of a new class of antibiotics called ketolides, was shown to be as eﬀective as 10-day courses of amoxicillin/ clavulanic acid, cefuroxime axetil, penicillin VK, and clarithromycin in the treatment of AECB, acute maxillary sinusitis, group A h-hemolytic streptococcus tonsillopharyngitis, and CAP, respectively [24–27]. Other potent

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TABLE 1 Intravenous and Oral Antimicrobials That Allow Once-Daily Dosing in the Treatment of CRTIs Antibacterial Intravenous Ceftriaxone Ertapenem Azithromycin Levofloxacin Gatifloxacin Moxifloxacin Oral Clarithromycin ER Azithromycin Telithromycin Levofloxacin Gatifloxacin Moxifloxacin Cefixime Ceftibuten

Once-Daily Dose 1g 1g 500 500 400 400

mg mg mg mg

500 250 800 500 400 400 400 400

2 2 1 1 1 1 1 1

mg mg mg mg mg mg mg mg

tablets tablets tablet tablet tablet tablet tablet tablet

antimicrobials such as gatiﬂoxacin and moxiﬂoxacin have also been studied for shorter 5-day courses in AECB and acute maxillary sinusitis and demonstrated good outcomes [28,29]. The macrolide, azithromycin, when administered for only 3 days, was shown to be as eﬀective as a 10-day course of amoxicillin/clavulanate in children with acute lower respiratory tract infections (i.e., community-acquired pneumonia) [30]. Of importance is the fact that the majority of isolated pathogens in this study were highly susceptible intracellular bacteria (i.e., Mycoplasma pneumoniae and Chlamydia pneumoniae) and viruses. More resistant pathogens such as S. pneumoniae and H. inﬂuenzae were not isolated; therefore, the eﬀect of a shorter course is not known for these bacteria. Azithromycin has also been approved as a single 30 mg/kg dose for the treatment of AOM in children [31]. The ability of many of the newer antimicrobials to be eﬀective over a shorter course is associated primarily with their increased microbiologic potency and improved pharmacokinetics. However, as resistant isolates become more prevalent, lengthier treatment regimens as well as higher doses of these agents will likely be needed to maintain eﬃcacy. Furthermore, although presumed to be less costly compared with longer course therapy due to increased patient compliance and equal eﬃcacy, pharmacoeconomic

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studies of these short-duration regimens are still needed to fully elucidate their economic impact. Transitional Therapy An important phase of Quintiliani and colleagues’ streamlining concept involved converting the treatment of a stable patient from an intravenous antibiotic to an active oral formulation in order to complete therapy at home. This usually took place around day seven [12]. Since the introduction of this concept in the late 1980s, it has been suggested that this intravenous to oral conversion can occur earlier, perhaps on day 3 or 4, or when certain clinical requirements are met [32–35]. Conversion from intravenous to oral antibiotics can result in important clinical and economic gains. Signiﬁcant cost reductions occur because of lower drug acquisition costs, a reduction in pharmacy and nursing time for preparation and administration of intravenous formulations, and most important, a potential reduction in the length of hospital stay. Additionally, an important beneﬁt derived from oral therapy is the elimination of the use of intravenous catheters, which are a signiﬁcant source of nosocomial bacteremias, especially those caused by staphylococci. It has been estimated that there are more than 20 million vascular catheters inserted annually in patients admitted to hospitals in the United States, resulting in more than 50,000 episodes of bacteremia or line sepsis. The frequency of these infections is directly correlated with the duration of their use. In a cost analysis of 104 patients with line sepsis, it was noted that the average additional cost from each episode of line sepsis was $3,707 (US, 1993) and even higher ($6,064) if it was caused by Staphylococcus aureus [36]. Intravenous to oral conversion of antimicrobials is known as transitional therapy and can further be identiﬁed by the type of conversion made: step-down therapy, switch therapy, or sequential therapy [16]. Step-down therapy involves conversion to an oral agent of the same or diﬀerent class but with less potency. An example of this is conversion from any parenteral hlactam to an oral one. Switch therapy refers to the conversion of an intravenous antimicrobial to a diﬀerent oral agent without reducing potency, such as the transition from intravenous ceftriaxone to oral ciproﬂoxacin to treat an Escherichia coli infection. Finally, conversion from a parenteral agent to its own oral formulation, without losing potency, is termed sequential therapy. Such is the case with the respiratory ﬂuoroquinolones, levoﬂoxacin, gatiﬂoxacin, and moxiﬂoxacin. Because of their high oral bioavailability, these agents would be expected to achieve similar serum concentrations regardless of the mode of administration [37,38]. Numerous studies have demonstrated cost savings when switch therapy is applied, speciﬁcally in the treatment of community-acquired pneumonia [33,35,39]. Despite strong clinical support, physician hesitancy still exists

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when converting patients to oral antibiotics, especially if a diﬀerent drug or class of drugs has to be used. Therefore, sequential therapy would be expected to have an advantage over switch or step-down therapy; the two formulations of a speciﬁc drug have similar adverse eﬀect proﬁles and the same susceptibility proﬁles, plus the oral formulation will often be signiﬁcantly less costly than its parenteral form. This was evaluated in a cost-eﬀectiveness analysis using results from a randomized, open-label, controlled trial comparing sequential oﬂoxacin versus standard switch therapy in patients hospitalized with complicated urinary tract infections, lower respiratory tract infections, or skin and soft tissue infections [40]. Success rates were similar between regimens; however, sequential oﬂoxacin therapy resulted in a one-day reduction in antibiotic-related hospitalization (a savings of $399 per patient, US, 1997). The investigators concluded that sequential therapy would lead to earlier oral conversion compared with switch therapy mainly because of an increased physician comfort level with using the same drug, only now in its oral formulation. Still, the greatest cost savings in the treatment of hospitalized patients occurs in the presence of a reduction in LOS. Even if treatment is switched to oral antibiotics for community-acquired pneumonia, this doesn’t automatically assure patient discharge from the hospital. It has been common practice to observe a patient for at least 24 hours after transitional therapy, usually to conﬁrm that the oral formulation is still eﬀective and well tolerated. However, this practice is based more on tradition than scientiﬁc evidence. Recently, several studies have conﬁrmed that this observational period is unnecessary and only increases hospital cost, including the risk of acquiring a nosocomial infection [41–43]. While applicable to many patients with moderate CAP, this observation may be signiﬁcantly diﬀerent when treating AECB or older patients with more severe CAP as many of these patients will have other comorbidities that may prolong their hospitalization course. Rhew and colleagues performed a retrospective review of ‘‘low-risk’’ patients with community-acquired pneumonia to assess the clinical beneﬁt of in-hospital observation after oral conversion. Low-risk patients were deﬁned as those patients with pneumonia in the absence of a serious comorbid disease (cancer, HIV, immunosuppression, organ transplantation, cystic ﬁbrosis, empyema, or lung cavity), infection with a high-risk pathogen, an obvious reason for continued hospitalization, or a life-threatening complication during hospitalization. Of 142 patients identiﬁed, 102 were observed and 40 were discharged as soon as oral antibiotics were initiated. No patient required medical intervention within 24 hours after hospital discharge and no patient from either group died within the 30-day followup period. The LOS for the observed and nonobserved groups was 98 F 33 hr and 83 F 49 hr, respectively. The diﬀerence in LOS was 15 hr (95%

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CI, 3 to 27 hr) and could translate into a cost savings of $550 per patient (US, 1993) [41]. A more recent observational study also found similar ﬁndings. Fortyeight percent of 266 patients with CAP were observed in-hospital for 24 hr or longer after switching from I.V. to oral antibiotic therapy, resulting in an unnecessary cost of approximately $119,370 (US, 2000). No underlying problem or comorbidity to justify continued hospitalization could be found. If these results were applied to all patients who were admitted to the hospital with CAP, 384,000 hospital days per year could be eliminated, resulting in savings of $265 million dollars [42]. It has been demonstrated that patients hospitalized with CAP generally become clinically stable on the third day of antimicrobial treatment, as indicated by an improvement in vital signs and ability to eat. More severe cases, such as in the elderly, patients with comorbidities, or those requiring ICU admission, can take longer to reach clinical stability (i.e., closer to 7 days) [34]. Initially, these time frames are useful to predict when patients should respond to therapy and would be candidates for transitional therapy. More speciﬁcally, vital signs, such as body temperature, systolic blood pressure, heart rate, and respiratory rate, plus the ability to tolerate oral intake would be the best markers to identify stable patients for conversion. Therefore, if a patient becomes stable as indicated by his or her vital signs on day one of treatment, there is no reason why oral therapy shouldn’t be initiated and the patient discharged home, provided no other comorbidities require hospitalization and close monitoring. Many institutions recommend that a pharmacist contact the physician with a recommendation for I.V. to oral conversion when such a patient is identiﬁed. Although usually eﬀective, this practice is time consuming and doesn’t assure that a candidate for transitional therapy will always be converted. Most studies that employ this technique have demonstrated acceptance in 80% of recommendations [33,35,44–47]. A more eﬃcient method would be to allow pharmacists to automatically convert candidates to an oral formulation of the same drug precisely when clinical stability is identiﬁed. This practice would assure conversion in all identiﬁed patients because the pharmacist enters the order on the spot. Pharmacist-managed automatic conversion programs have been developed at several institutions with positive outcomes [48,49]. Kuti and colleagues performed an economic evaluation of the intravenous to oral conversion program for levoﬂoxacin at their institution and compared this with a prospective observational period before implementation [49]. The majority of patients evaluated had a diagnosis of CAP or AECB. Of patients who met conversion criteria (temperature, HR, RR, BP, oral intake), 92% were converted when the pharmacists managed the pro-

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gram as compared with 37% beforehand, P = 0.009 (Fig. 2). Moreover, patients were converted earlier during the pharmacist-managed program, 3.65 days versus 7.09 days, P = 0.010. As a result, level 1, 2, and 3 costs were signiﬁcantly reduced by the program. The average cost of a hospital stay for a patient meeting criteria was $3,267 (US, 2000) less after the pharmacistmanaged program was implemented. This was predominantly due to a reduction in hospital LOS, 6 days versus 9.5 days, P = 0.031. Pharmacoeconomics of Clinical Pathways Despite all these methods for reducing the cost associated with antimicrobial treatment of CRTIs, little savings will be seen if they are not in turn applied to patient care. This can best be accomplished with implementation of guidelines, otherwise known as clinical pathways, for the treatment of these infections in a speciﬁc institution or outpatient setting. Originally developed by industry, clinical pathways are frequently used by health care systems to ensure optimum delivery of high-quality care and control costs. These pathways can include guidelines for ranking patient severity, recommendations whether or not to admit the patient, appropriate diagnostic tests to be ordered, and recommended treatment options. For CRTIs, clinical pathways can also include cost-eﬀective recommendations such as the proper dose, most eﬀective method of administration, and even criteria for oral conversion and hospital discharge. All of these recommendations should provide for the highest quality and most cost-eﬀective treatment of patients. Clinical pathways may also have positive eﬀects on the time to ﬁrst antibiotic dose and hospital LOS [50,51]. Marrie and colleagues evaluated

FIGURE 2 Cumulative percent of patients converted to oral levofloxacin over the first eight days of therapy. (From Ref. 49.)

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the eﬀect of a clinical pathway incorporating the Pneumonia Severity Index Scoring System [52] and intravenous or oral levoﬂoxacin in 19 Canadian teaching or community hospitals. Hospitals were randomized to either introduce the developed clinical pathway or continue conventional management. No diﬀerence between quality of life, occurrence of complications, readmission, or mortality was observed between clinical pathway and conventional treatment sites. Pathway use was associated with a 1.7 day reduction in bed days per patient managed (BDPM), which is the product of the institutional average length of stay and the admission rate (4.4 versus 6.1 days, P = 0.04). Clinical pathway institutions also realized a reduction in median LOS (5.0 versus 6.7, P = 0.01) and 1.7 fewer days of intravenous antibiotic therapy (4.6 versus 6.3 days, P = 0.01). Although no formal economic analysis was included in this article, the investigators estimated that the reduction in use of hospital resources has the potential of saving approximately $1,700 (US, 2000) per patient treated [50]. Marrie and colleagues used levoﬂoxacin as the antimicrobial agent of choice for their CAP clinical pathway. Certainly, any other respiratory ﬂuoroquinolone, such as moxiﬂoxacin and gatiﬂoxacin, would be expected to have similar outcomes. Likewise, antibiotics in other classes such as h-lactams/ macrolide combinations and telithromycin can also be equally included in a clinical pathway. The choice of antibiotic should depend on the types of patients being treated and the resistance rates speciﬁc to that area. Thus, if pneumococcal resistance to the h-lactam antibiotics were prevalent in an area, the most cost-eﬀective agent would be a respiratory ﬂuoroquinolone or telithromycin. These agents have activity against the most likely causative pathogens in CRTIs, including penicillin-resistant isolates as well as h-lactamase– producing H. infuenzae and M. catarrhalis, can be dosed once-daily to improve compliance, and are available in an oral formulation with excellent bioavailability. However, if resistance is not an issue in a speciﬁc institution, then a h-lactam, a macrolide, or both can be included on the clinical pathway. Recommendations can be based on numerous guidelines currently available for the treatment of CAP, AECB, and acute bacterial rhinosinusitis [3,53–56]. Combination therapy should be streamlined as soon as a pathogen is isolated, and parenteral agents, if used initially, should be transitioned to appropriate oral formulations when patients become stable. Finally, patient discharge immediately after oral conversion should be encouraged in order to reduce LOS, provided no other comorbidities require additional in-hospital monitoring. CONCLUSION Despite the advances in new therapies and approaches to diagnosis, the management of CRTIs remains a clinical and economic challenge. The

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concepts outlined within this discussion may be used as a guideline to create a strategic and economical approach to the management of these infections, speciﬁcally in the era of increasing antimicrobial resistance. As mentioned earlier in this chapter, acquisition costs alone do not accurately depict the total economic impact associated with the management of CRTIs. The most beneﬁcial approach to therapy is one that produces a rapid, positive clinical outcome. Ultimately, rapid cure will also lead to positive economic outcomes, beneﬁting the patient, the institution, and society.

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43. Beaumont M, Schuster M. Is an observation period necessary after intravenous antibiotics are changed to oral administration? Am J Med 1999; 106:114–116. 44. Prybylski KG, Rybak MJ, Martin PR, Weingarten CM, Zaran FK, Stevenson JG, et al. A pharmacist-initiated program of intravenous to oral antibiotic conversion. Pharmacotherapy 1997; 17:271–276. 45. Ahkee S, Smith S, Newman D, Ritter W, Burke J, Ramirez JA. Early switch from intravenous to oral antibiotics in hospitalized patients with infections: a 6month prospective study. Pharmacotherapy 1997; 17:569–575. 46. Gums JG, Yancey RW, Hamilton CA, Kubilis PS. A randomized, prospective study measuring outcomes after antibiotic therapy intervention by a multidisciplinary consult team. Pharmacotherapy 1999; 19:1369–1377. 47. Sevine F, Prins JM, Koopmans RP, Langendijk PNJ, Bossuyt PMM, Dankert J, et al. Early switch from intravenous to oral antibiotics: guidelines and implementation in a large teaching hospital. J Antimicrob Chemother 1999; 43:601– 606. 48. Wong-Beringer A, Nguyen KH, Razeghi J. Implementing a program for switching from i.v. to oral antimicrobial therapy. Am J Health Syst Pharm 2001; 58: 1139–1142. 49. Kuti JL, Le TN, Nightingale CH, Nicolau DP, Quintiliani R. Pharmacoeconomics of a pharmacist-managed program for automatically converting levoﬂoxacin route from i.v. to oral. Am J Health Syst Pharm 2002; 59:2209–2215. 50. Marrie TJ, Lau CY, Wheeler SL, Wong CJ, Vandervoort MK, Feagan BG. A controlled trial of a critical pathway for treatment of community-acquired pneumonia. JAMA 2000; 283:749–755. 51. Benenson R, Magalski A, Cavanaugh S, Williams E. Eﬀects of a pneumonia clinical pathway on time to antibiotic treatment, length of stay, and mortality. Acad Emerg Med 1999; 6:1243–1248. 52. Fine MJ, Auble TE, Yealy DM, Donald M, Hanusa BH, Weissfeld LA, et al. A prediction rule to identify low-risk patients with community-acquired pneumonia. N Engl J Med 1997; 336:243–250. 53. Niederman MS, Mandell LA, Anzueto A, Bass JB, Broughton WA, Campbell GD, et al. Guidelines for the management of adults with community-acquired pneumonia: diagnosis, assessment of severity, antimicrobial therapy, and prevention. Am J Respir Crit Care Med 2001; 163:1730–1754. 54. Mandell LA, Marrie TJ, Grossman RF, Chow AW, Hyland RH. Canadian guidelines for the initial management of community-acquired pneumonia: an evidence based update by the Canadian Infectious Diseases Society and the Canadian Thoracic Society. Clin Infect Dis 2000; 31:383–421. 55. Heﬀelﬁnger JD, Dowell SF, Jorgensen JH, Klugman KP, Mabry LR, Musher DM, et al. Management of community-acquired pneumonia in the era of pneumococcal resistance: a report from the Drug-Resistant Streptococcus pneumoniae Therapeutic Working Group. Arch Intern Med 2000; 160:1399–1408. 56. Sinus and Allergy Health Partnership. Antimicrobial treatment guidelines for acute bacterial rhinosinusitis. Otolaryng Head Neck Surg 2000; 123:S4–S32.

4 The Role of Macrolides in the Treatment of Community-Acquired Pneumonia William R. Bishai Johns Hopkins School of Medicine Baltimore, Maryland, U.S.A.

Charles H. Nightingale Hartford Hospital, Hartford and University of Connecticut School of Pharmacy Storrs, Connecticut, U.S.A.

Erythromycin, the ﬁrst member of the macrolide class to enter clinical use, was introduced in 1952. Erythromycin remained a mainstay antibiotic for several decades both as an inpatient, infusible agent and as an outpatient, orally administered drug until the introduction of the newer macrolide and azalide agents, clarithromycin and azithromycin, in the early 1990s. The macrolide antibiotic class has activity against each of the major pyogenic pathogens playing etiologic roles in respiratory tract infections: Streptococcus pneumoniae, Haemophilus inﬂuenzae, and Moraxella catarrhalis. Moreover, they are potent against atypical respiratory tract pathogens: Legionella pneumophila, Mycoplasma pneumoniae, and Chlamydia pneumoniae. As such they comprise a class of agents with focused activity against respiratory pathogens. It is important to note that they have little role in the treat59

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ment of skin and soft tissue infections for which staphylococci are common causes, enteric infections caused by gram-negative bacilli, or opportunistic gram-negative infections such as Pseudomonas aeruginosa. Hence, macrolides are considered excellent focused therapy agents for use against respiratory tract infections. MACROLIDE PK/PD RELATIONSHIPS Despite being related structurally and by mechanism of action, the pharmacodynamic parameters most predictive of success are diﬀerent for the major drugs in the macrolide/azalide family. For clarithromycin and erythromycin (as with the h-lactams), time above MIC seems to be the critical parameter; for azithromycin the AUC/MIC ratio seems to be most predictive. For optimal eﬃcacy against S. pneumoniae, clarithromycin and erythromycin should achieve concentrations above the MIC for greater than 40% of the dosing interval [1]; and for azithromycin an AUC/MIC ratio above 25 is optimal [2]. Beyond pharmacodynamics, clarithromycin and azithromycin have dramatically diﬀerent human pharmacokinetics (Fig.1). The Cmax achieved with a 500 mg oral dose of clarithromycin is approximately 2.5 Ag/mL with a half-life of 6 hr [3]. Thus, this agent achieves a concentration above 1 Ag/mL, which is the current NCCLS breakpoint between intermediate and high level clarithromycin resistance, for greater than 50% of a 12-hr treatment cycle. Likewise, extended-release clarithromycin achieves a Cmax of 2.5 Ag/mL with a half-life of 12–16 hr, also providing drug concentrations well above the MIC of intermediately resistant organisms for greater than half of its 24-hr treatment cycle. In contrast, the Cmax of azithromycin is only 0.4 Ag/ mL with an AUC of 4.5 mg-h/mL following administration of a 500 mg dose [3]. Thus, for isolates with an MIC of less than 0.25 Ag/mL, azithromycin achieves the target AUC/MIC ratio needed for optimal eﬃcacy in the serum; however, for isolates with higher MICs, eﬀectiveness may be less. Beyond serum concentration, however, macrolides may exert their potency through a high degree of tissue penetration in the respiratory tract. This phenomenon is combined with the fact that pyogenic respiratory tract pathogens such as S. pneumoniae, H. inﬂuenzae, and M. catarrhalis are extracellular agents that induce disease by infection in the alveolar spaces or on mucosal surfaces. Appreciation of this fact has prompted an investigation of macrolide drug levels in key compartments such as the epithelial surface and the intracellular space of leukocytes and macrophages, which are recruited to the site of infection [4,5]. As seen in Figure 2, concentrations of clarithromycin and azithromycin in the epithelial lining ﬂuid (ELF) are typically approximately 10 times higher than the achievable serum levels

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FIGURE 1 Plasma concentrations of clarithromycin and azithromycin during the treatment cycle with standard U.S. dosing of 500 mg twice daily and 250 mg once daily, respectively. For comparison, the NCCLS MIC90 breakpoints between susceptible and nonsusceptible strains of Streptococcus pneumoniae are shown for the two agents in dotted lines. (From Ref. 43.)

[6,7]. Clarithromycin, after standard dosage, achieves ELF levels of approximately 35 Ag/mL and alveolar macrophage intracellular concentrations of approximately 350–500 Ag/mL 6 hr after oral dosage in humans [6]. Twentyfour hours after oral dosing, the ELF concentration is approximately 4.5 Ag/ mL and the alveolar macrophage concentration 100 Ag/mL. Azithromycin achieves ELF levels of 1–2 Ag/mL but much higher levels in the alveolar macrophage intracellular compartment [6]. A number of investigators have emphasized that the presence of inﬂammation, which recruits leukocytes to the site of infection, enhances the bioavailability of macrolides, in particular that of azithromycin [8–10]. Levels of azithromycin inside neutrophils and monocytes have been measured at 10 Ag/mL or higher, suggesting that these cells may be an important source of macrolide drug during inﬂammation [4]. By taking into account macrolide concentrations in the epithelial lining ﬂuid, it is apparent that sustained concentrations of greater than 25 to 35 Ag/ mL may be achieved in the ELF with clarithromycin for a greater than 50% of the treatment cycle. Because more than 90% of the S. pneumoniae isolates in the United States have MICs to clarithromycin of 16 Ag/mL or less, the

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FIGURE 2 Lung epithelial lining fluid (ELF) concentrations of clarithromycin and azithromycin during the treatment cycle with standard U.S. dosing of 500 mg twice daily and 250 mg once daily, respectively. For comparison, the NCCLS MIC90 breakpoints between susceptible and nonsusceptible strains of Haemophilus influenzae are shown for the two agents in dotted color-coded lines for the two drugs, and the clarithromycin NCCLS MIC90 breakpoints between susceptible and nonsusceptible strains of Streptococcus pneumoniae are also shown. (From Ref. 43.)

pulmonary concentration eﬀect of macrolides may well explain their continued treatment eﬃcacy despite the emergence of strains that are deﬁned as resistant by current NCCLS breakpoints. BACTERIAL RESISTANCE TO THE MACROLIDES S. pneumoniae Resistance Mechanisms to Macrolides Macrolide resistance in the United States is currently approximately 20–26% in recent surveillance studies [11–13]. Among S. pneumoniae isolates resistant to penicillin, macrolide coresistance is approximately 75% [11]. In parts of southern Europe and in the Far East, macrolide resistance rates of 75% or greater have been reported [14]. Pneumococcal resistance to the macrolides falls into two categories. Relatively low level resistance with MICs from 1 to 32 Ag/mL are observed with pneumococcal isolates harboring macrolide eﬄux pump genes (mef

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genes). These pump genes show inducible activity and are capable of pumping macrolides drugs out of the bacterial cell in a concentration-dependent manner. Newer ketolide drugs, such as telithromycin, are not substrates of the mef eﬄux pumps currently present in pneumococci, and hence they remain active in pneumococci expressing mef genes. The second mechanism of resistance occurs via target modiﬁcation. Erythromycin ribosomal methylase (erm) genes of several diﬀerent types are capable of methylating key residues in the ribosomal RNA of the 50S ribosome, rendering the ribosomal binding pocket of macrolides nonsusceptible to macrolide inhibition. This form of resistance is concentrationindependent and confers MICs of greater than 64 Ag/mL to pneumococci. Many of the erm genes identiﬁed in pneumococci are also inducible following the administration of macrolide drugs. In addition to the genotypic categorization of pneumococcal resistance to macrolides, there is a phenotypic resistance system. MLSB phenotypic resistance indicates coresistance to macrolides, lincosamides, and streptogramins, and is generally synonymous with target modiﬁcation mechanisms with the erm genotype. The M phenotype of pneumococcal macrolide resistance represents resistance to macrolides only, without lincosamide and streptogramin resistance. Such isolates are susceptible to the lincosamide drug clindamycin, while resistant to erythromycin and other macrolides. Usually, M-type resistance correlates with the presence of an eﬄux pump– based mechanism with a mef genotype. In the United States, approximately 60 to 75% of macrolide-resistant strains are the M phenotype with an eﬄux-based mechanism of resistance and MICs between 1 and 32 Ag/mL. Only about 25% of isolates are of the high level resistance, MLSB phenotype with MICs of greater than 64 Ag/mL [15]. There is some evidence that while the rate of MLSB resistance is remaining relatively stable, there has been a gradual shift toward higher MIC levels of resistance within the M-phenotype strains, with an increasing proportion of strains with MICs of 8 or 16 Ag/mL observed in recent surveys [15]. In contrast to the situation in the United States, in southern Europe and in other parts of the world there appears to be a higher rate of MLSB macrolide resistance. In fact, some studies have identiﬁed 75 to 80% MLSB (or erm-based) resistance to the macrolides [14]. The new ketolide agent, telithromycin, which is a 14-membered ring macrolide derivative, is active against the majority of MLSB and M-phenotype pneumococcal isolates. In addition telithromycin is not an inducer of the mef and erm genes [16]. However, there have been reports of in vitro–derived resistance [17], and some clinical isolates have been identiﬁed with telithromycin resistance of 1 to 8 Ag/mL, which may be due to a mutation in the ribosomal L4 protein [18].

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Macrolide Immunomodulatory Effects An interesting drug-host interaction has been demonstrated for some macrolides, showing that the drug may have an immune-enhancing eﬀect in addition to its direct antibacterial eﬀect [5]. It has been shown that macrolides enhance ciliary clearance and reduce levels of proinﬂammatory cytokines, which may reduce the recruitment of tissue-damaging mononuclear cells to the site of resolving infection and accelerate recovery. Such immunomodulatory abilities may signiﬁcantly augment the activity of an antibiotic and may account for high treatment success rates even when there is relative antimicrobial resistance.

IN VIVO–IN VITRO PARADOX WITH PNEUMOCOCCAL RESPIRATORY TRACT INFECTIONS Despite rising rates of pneumococcal resistance to h-lactam and macrolide antibiotics, there remains little evidence that this microbiologic phenomenon is correlated with increased rates of treatment failure. The controversy brings into focus the question of whether microbiologic resistance determinations in vitro, in fact, predict treatment outcomes in vivo. A number of large-scale clinical studies in community-acquired pneumonia due to S. pneumoniae have looked for inferior treatment outcomes with drug-resistant S. pneumoniae (DRSP) infections compared with drug susceptible. The In Vivo–In Vitro Paradox with Penicillin-Resistant S. Pneumoniae (PRSP) The ﬁrst study to evaluate this question was conducted in Barcelona in a series of 504 patients with culture-proven pneumococcal pneumonia [19]. Although this study contained a high proportion of penicillin-resistant isolates, there was no increase in mortality in patients who had DRSP compared with those who had drug-susceptible isolates. Moreover, the use of discordant therapy in the study during the ﬁrst 48 hours was not associated with an increase in mortality compared with concordant therapy. More recently Feikin et al. evaluated the clinical impact of resistance in the United States and Canada from 1995 to 1997, identifying a series of 5837 cases of community-acquired invasive pneumococcal pneumonia. The study did not identify a statistically signiﬁcant diﬀerence in the mortality rate between penicillin-susceptible infection and penicillin-resistant infection [20]. Numerous other such studies have been conducted, and several have looked at nonmortality measures of outcome (Table 1). In general, there has been no consistent eﬀect on either morbidity or mortality in pneumonia due to

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TABLE 1 Studies Comparing Mortality Outcomes of Invasive Pneumococcal Pneumonia Caused by Penicillin-Susceptible (Pen-S) and Penicillin-NonSusceptible (Pen-NS) Strains

Location

Year

Barcelona, Spain Israel

1984–93 1987–92

Ohio

1991–94

New Yorka

1992–96

S. Africa (children) Atlanta

1993–94

North America

1995–97

Barcelona

1996–98

1994

Fraction of patients with DRSP 145/504 (29%) 67/293 (23%) 39/499 (8%) 30/421—Pen IR (7%) 19/421—Pen R (5%) 35/108 (32%) 44/192 (23%) 741/4193 (18%) 49/101—Pen (49%) 12/101—Mac (12%)

Mortality Pen-S

Pen-NS

P value

Reference

24%

38%

NS

11%

16%

NS

19%

21%

NS

14%

27%

NS

Pallares et al. (Ref. 19) Rahav et al. (Ref. 38) Plouffe et al. (Ref. 39) Turett et al. (Ref. 21)

16%

42%

<0.01

16%

24%

NS

11%

23%

NS

11%

14%

NS

6%

16%

NS

14%b

7%c

NS

Friedland et al. (Ref. 40) Metlay et al. (Ref. 41) Feikin et al. (Ref. 20) Ewig et al. (Ref. 42)

a

70% of patients with the Pen-NS strains were HIV-infected. Mac-S. c Mac-NS Source: Ref. 22. b

h-lactam–resistant S. pneumoniae, although one study with small numbers of patients with a high rate of HIV infection did identify a mortality diﬀerence [21]. These ﬁndings have been recently summarized [22]. The In Vivo–In Vitro Paradox with Macrolide-Resistant S. Pneumoniae (MRSP) Similar scrutiny has been applied to the outcome of pneumonia due to macrolide-resistant S. pneumoniae (MRSP). Ewig et al. evaluated 101 consecutive patients in Barcelona between 1996 and 1998, 47% of whom had bacteremic pneumococcal pneumonia. In the study there was no statistically signiﬁcant diﬀerence in mortality comparing pneumonia due to penicillinsusceptible S. pneumoniae (mortality 6%) and penicillin-nonsusceptible S.

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pneumoniae (mortality 16%). The investigators looked at the impact of macrolide resistance in the study. The mortality rate among patients with macrolide-susceptible isolates was 14% (10 deaths among 74 patients evaluated), whereas the mortality among patients with macrolide nonsusceptible isolates was 7% (2 deaths among 27 patients with MRSP), a result that was a trend in the counterintuitive direction but did not achieve statistical signiﬁcance. Thus, as with h-lactam resistance, to date there has been no demonstration of statistically worse outcomes for mortality or morbidity with macrolide-resistant pneumococcal pneumonia. Descriptive Reports of Macrolide Failures Associated with Bacteremic Pneumococcal Pneumonia Pharmacodynamic considerations would predict that while the macrolides should have excellent eﬃcacy for tissue-based pneumonia, they might have less activity in bacteremic pneumonia because of their relatively lower serum drug levels compared with tissue levels. Several recent case reports and small case series have documented pneumococcal bacteremia due to resistant isolates associated with macrolide therapy [23–29]. Typically such failures occur in outpatients receiving oral macrolides, and the failures have been identiﬁed with isolates having MICs of 8 Ag/mL or higher [25,28], although in one case, failure with breakthrough bacteremia was seen during parenteral macrolide therapy with azithromycin [29]. A recent case-control report by Lonks and colleagues evaluated patients treated with macrolides over a 13-year period in four study sites in Boston, Providence, and Barcelona. The study found that concurrent exposure to macrolides increased the likelihood of having macrolide intermediate-resistant S. pneumoniae (MISP) or fully macrolide resistant S. pneumoniae (MRSP) compared with age- and sex-matched controls [25]. The study suggested that macrolide resistance resulting from eﬄux strains of the M phenotype (low-level resistance with MICs of 1 to 16 Ag/mL) was clinically relevant. However, evaluation of the data identiﬁed that only ﬁve instances of nonmeningeal breakthrough bacteremia due to M-phenotype strains were observed. For two of these, no MIC data were included, two had MICs of 16 Ag/mL, and only one had an MIC of 4 Ag/mL (which is in the range commonly observed with eﬄux strains in the United States). Moreover, the patient for whom the latter isolate was obtained had been treated with his ﬁrst macrolide dose within hours of the positive blood culture. Hence, these data do not conclusively link macrolide treatment failure with pneumonia caused by pneumococci with M-type (low level resistance) phenotypic resistance. Unfortunately, these anecdotal and small series reports lack incidence information because they do not include a denominator to suggest how

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common these occurrences are. Clearly more information and prospective studies will be needed to assess this important question.

COMMUNITY-ACQUIRED PNEUMONIA GUIDELINES AND MACROLIDES Three Sets of Community-Acquired Pneumonia Guidelines in the United States Although ATS was the ﬁrst to write CAP guidelines in 1993, that document has been sorely out of date since it predated the introduction of respiratory ﬂuoroquinolones. The IDSA introduced its CAP guidelines 5 years later in 1998. However, as resistance rates in respiratory tract infections have risen and more drugs have become available, there has been increasing pressure to generate new or updated practice recommendations. In 2000, CDC guidelines appeared in May [30], and updated IDSA Guidelines were published in September [31]. Updated ATS guidelines, which appeared in June 2001, are now the third major set of CAP guidelines to appear in the span of 13 months [32]. The market for respiratory tract antibiotics is estimated to approach $10 billion annually. Within this pie, the greatest fraction of antibiotic use and expenditure lies within outpatient management of respiratory tract infections. It is in this same arena that empiric management plays an important role, because in routine clinical practice, cultures and antimicrobial susceptibility testing, if performed, usually have a minimal impact on the clinical course. CAP guidelines, such as the new ATS statement, have their greatest inﬂuence in directing empiric management—particularly in outpatient practice. The rising rates of resistance among respiratory tract pathogens, particularly the pneumococcus, are a major concern addressed by each of the guidelines. Although rates of microbiologic resistance have increased, all three guidelines speciﬁcally point out that there has not been a proven correlation between microbiologic resistance and loss of clinical eﬃcacy among older drug classes such as the h-lactams, macrolides, and doxycycline. The paradox between increasing rates of microbiologic resistance but stable rates of therapeutic success has prompted a number of experts to question the current trend towards using new drug categories, such as the ﬂuoroquinolones, when treatment failure is not being seen with older agents. There has been a steady trend toward greater stratiﬁcation of patient categories in respiratory tract infections. The Fine criteria [33,34] gave methodologic criteria for stratifying patients with pneumonia to four categories depending on severity. Both the IDSA and the ATS guidelines are based on categories developed by Fine risk stratiﬁcation with pneumonia. The IDSA

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TABLE 2

Bishai and Nightingale Recommendations for Outpatient Management of CAP

Guideline body Date CDC IDSA ATS

Antibiotic Category Recommended

5/00 Macrolidea or Doxycycline or h-lactamb 9/00 Macrolide or Doxycycline or Fluoroquinolonec 6/01 Uncomplicated: Macrolide or Doxycycline Complicated: Fluoroquinolone alone or a h-lactamd plus either a Macrolide or Doxycycline

Reference 30 31 32

a

Recommended macrolides: clarithromycin, erythromycin, or azithromycin. Recommended h-lactams: amoxicillin, amoxicillin/clavulanate, cefuroxime axetil, cefpodoxime, or cefprozil. Cefdinir, a new agent, also acceptable. c Recommended fluoroquinolones: levofloxacin, gatifloxacin, or moxifloxacin. d Recommended h-lactams: cefpodoxime, cefuroxime, amoxicillin (3 g/day), or amoxicillin/ clavulanate. Cefdinir, a new agent, also acceptable. b

guidelines used three severity categories, whereas the new ATS guidelines have six: two for outpatients and four for inpatients. Signiﬁcantly, the ATS guidelines are the ﬁrst to subdivide the all-important category of outpatient CAP. As may be seen in Table 2, the four categories of drugs recommended for outpatient CAP management are: (1) macrolides, (2) ﬂuoroquinolones, (3) certain h-lactams, and (4) doxycycline. Comparison of the guidelines reveals several areas of discrepancy in managing outpatients with CAP. Signiﬁcantly, all three guideline bodies recommend macrolides (clarithromycin, erythromycin, or azithromycin) or doxycycline for managing outpatient CAP. The drugs for which there is disagreement are the h-lactams and ﬂuoroquinolones. ROLE FOR h -LACTAM MONOTHERAPY IN CAP GUIDELINES? The CDC guidelines have suggested that certain h-lactam drugs are eﬀective in outpatient CAP, but there is considerable concern over their lack of activity against the causative agents of atypical pneumonia such as Legionella and Mycoplasma pneumoniae. Some studies of CAP suggest that mycoplasma may be more prevalent in older individuals than reported earlier [35]. Among the h-lactam agents with relatively high activity against S. pneumoniae, H. inﬂuenzae, and M. catarrhalis that are deemed appropriate under the CDC guidelines are amoxicillin, amoxicillin/clavulanate, cefuroxime axetil, cefpodoxime, or cefprozil. The new agent, cefdinir, has potency and pharmacoki-

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69

netic properties which make it acceptable as well. Monotherapy with a hlactam in CAP is not recommended by ATS or IDSA. Macrolides Versus Fluoroquinolones as First-Line Agents for the Empiric Management of Outpatient CAP One of the most pressing issues in the outpatient management of communityacquired pneumonia is the appropriate use of ﬂuoroquinolones. While all three guideline groups—CDC, IDSA and ATS—have recommended ﬂuoroquinolones for inpatient management of community-acquired pneumonia, they have disagreed over the appropriate role for these drugs on the outpatient side. The respiratory ﬂuoroquinolones levoﬂoxacin, gatiﬂoxacin, and moxiﬂoxacin have gained popularity because of their broad spectrum of action, their convenience of dosing, and the convenience of dual I.V. and P.O. dosing routes. The IDSA guidelines, which endorsed the outpatient use of ﬂuoroquinolones in CAP, emphasized the rising rates of pneumococcal resistance to macrolides and doxycycline. Concern over the possibility of treatment failure due to resistance has fueled the popularity of ﬂuoroquinolones for respiratory tract infections. Current rates of resistance to the ﬂuoroquinolones among respiratory tract pathogens are low. For Streptococcus pneumoniae, U.S. rates of ﬂuoroquinolone resistance remain under 5%. This contrasts with higher rates of microbiologic resistance to the macrolides among pneumococci of approximately 25%. Despite the relatively high rate of microbiologic resistance to the macrolides, the ATS guidelines point out that treatment failure has not been observed at an appreciable rate in spite of the growing rate of resistance. The ATS and the CDC have been concerned that expanded use of the ﬂuoroquinolones for outpatient management of respiratory tract infection may be unnecessary and could accelerate the emergence of resistance to this class, thereby damaging the future usefulness of the ﬂuoroquinolone category. Out of concern over the emergence of new resistance, the CDC guidelines took a conservative approach, recommending strict restrictions on the use of ﬂuoroquinolones for empiric management of outpatient CAP. The CDC has recommended that outpatient use of ﬂuoroquinolones be restricted to patients known (1) to be allergic to all other agents, (2) to have a highlevel drug resistant strain, or (3) to have had previous treatment failure. On the other hand, the IDSA guidelines took the opposite stand, recommending use of ﬂuoroquinolones for empiric management of outpatient pneumonia with no restriction. The ATS guidelines recommend an intermediate approach by restricting ﬂuoroquinolones for uncomplicated outpatient CAP, but endorsing their

70

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use in high-risk patients with CAP being managed as outpatients. The ATS deﬁnes high-risk patients as those with preexisting COPD, immunosuppression, recent hospitalization, or residence in a chronic care facility. For such complicated CAP patients, the ATS recommends one of two regimens: (1) a hlactam plus either a macrolide or doxycycline, or (2) a respiratory ﬂuoroquinolone. For uncomplicated CAP, the ATS guidelines recommend that a macrolide or doxycycline be used in the interest of restricting ﬂuoroquinolones to prevent the emergence of resistance. Issues in Appropriate Use of Antibiotics Underlying the diﬀerences in these guidelines is a controversy among infectious diseases and pulmonary experts on just when resistance may be expected to emerge in respiratory tract pathogens. Leading the list of pathogens in this arena is Streptococcus pneumoniae, in which we have witnessed the emergence of alarming levels of resistance (35% to penicillin, 25% to macrolides) over the past decade. Looking back, historically, few pathogen-drug combinations have escaped the inexorable emergence of resistance. (Notable exceptions to the generalization that increased use produces increased resistance are Streptococcus pyogenes and Treponema pallidum, which have remained uniquely susceptible to penicillin for over 50 years.) Thus, we have learned that increased use eventually leads to resistance. With regard to penicillin resistance in the pneumococcus, it is perhaps a more intriguing question to consider why it took 40 years for this resistance to occur beginning in the early 1990s despite high-level use of h-lactam drugs. Here an important observation has been made from the molecular epidemiologic studies of pneumococcal spread in the United States. The majority of drug-resistant S. pneumoniae (DRSP) strains in North America belong to one of six serotypes [36]. Hence, the increased prevalence of DRSP is due to clonal spread. The fact that additional pneumococcal serotypes have not acquired mutations conferring h-lactam resistance suggests a signiﬁcant genetic barrier to achieving resistance. Unlike h-lactam resistance, pneumococcal ﬂuoroquinolone resistance in North America has been polyclonal and associated with multiple strains independently acquiring, or mutating to, the resistance phenotype. In Canada, where ciproﬂoxacin was used extensively for the treatment of respiratory tract infections beginning in the late 1980s and throughout the 1990s, multiple DNA ﬁngerprint types and multiple serotypes of ﬂuoroquinolone-resistant pneumococci have been observed [37]. These data suggest that the barrier to resistance development in the pneumococcus is substantially lower for the ﬂuoroquinolones than it is for the h-lactam drugs. With lower genetic barriers to developing resistance, the emergence of quinolone

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71

resistance in pneumococci may occur more rapidly under conditions of expanded use than was witnessed with h-lactams. Guidelines have emerged as an inﬂuential part of clinical practice during the past decade. The CDC, IDSA, and ATS guidelines for the management of community-acquired pneumonia represent scholarly contributions and oﬀer rational approaches on the empiric management of outpatient community acquired pneumonia. One lingering concern is the number of diﬀerent guidelines on the same topic and the lack of complete consensus on the topic of ﬂuoroquinolone use in CAP. There has been a considerable interest in combining the expert societies in future years to publish a single set of guidelines rather than multiple independent, and sometimes conﬂicting, documents. Indeed, plans are currently in progress to achieve such a consensus statement, which will be endorsed by the ATS, CDC, and IDSA.

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Craig WA. Pharmacokinetic/pharmacodynamic parameters: rationale for antibacterial dosing of mice and men. Clin Infect Dis 1998; 26:1–10. 2. Craig WA. The hidden impact of antibacterial resistance in respiratory tract infection. Re-evaluating current antibiotic therapy. Respir Med 2001; 95(suppl A):S12–S19. 3. Carbon C. Pharmacodynamics of macrolides, azalides, and streptogramins: eﬀect on extracellular pathogens. Clin Infect Dis 1998; 27:28–32. 4. Amsden GW. Pneumococcal macrolide resistance—myth or reality? J Antimicrob Chemother 1999; 44:1–6. 5. Baldwin DR, Honeybourne D, Wise R. Pulmonary disposition of antimicrobial agents: methodological considerations. Antimicrob Agents Chemother 1992; 36:1171–1175. 6. Rodvold KA, Gotfried MH, Danziger LH, Servi RJ. Intrapulmonary steadystate concentrations of clarithromycin and azithromycin in healthy adult volunteers. Antimicrob Agents Chemother 1997; 41:1399–1402. 7. Patel KB, Xuan D, Tessier PR, Russomanno JH, Quintiliani R, Nightingale CH. Comparison of bronchopulmonary pharmacokinetics of clarithromycin and azithromycin. Antimicrob Agents Chemother 1996; 40:2375–2379. 8. Girard AE, Cimochowski CR, Faiella JA. Correlation of increased azithromycin concentrations with phagocyte inﬁltration into sites of localized infection. J Antimicrob Chemother 1996; 37(suppl C):9–19. 9. Ballow C, Amsden GW, Highet VS. Healthy volunteer pharmacokinetics of oral azithromycin in serum, urine, polymorphonuclear leukocytes and inﬂammatory vs. non-inﬂammatory skin blisters. Clinical Drug Investigation 1998; 15: 159–167. 10. Freeman CD, Nightingale CH, Nicolau DP, Belliveau PP, Banevicius MA, Quintiliani R. Intracellular and extracellular penetration of azithromycin into

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resistance among Streptococcus pneumoniae isolates from blood cultures from Providence, R.I. Antimicrob Agents Chemother 1993; 37:1742–1745. Lonks JR, Garau J, Gomez L, et al. Failure of macrolide antibiotic treatment in patients with bacteremia due to erythromycin-resistant Streptococcus pneumoniae. Clin Infect Dis 2002; 35:556–564. Fogarty C, Goldschmidt R, Bush K. Bacteremic pneumonia due to multidrugresistant pneumococci in 3 patients treated unsuccessfully with azithromycin and successfully with levoﬂoxacin. Clin Infect Dis 2000; 31:613–615. Kelley MA, Weber DJ, Gilligan P, Cohen MS. Breakthrough pneumococcal bacteremia in patients being treated with azithromycin and clarithromycin. Clin Infect Dis 2000; 31:1008–1011. Waterer GW, Wunderink RG, Jones CB. Fatal pneumococcal pneumonia attributed to macrolide resistance and azithromycin monotherapy. Chest 2000; 118:1839–1840. Musher DM, Dowell ME, Shortridge VD, et al. Emergence of macrolide resistance during treatment of pneumococcal pneumonia. N Engl J Med 2002; 346:630–631. Heﬀelﬁnger JD, Dowell SF, Jorgensen JH, et al. Management of communityacquired pneumonia in the era of pneumococcal resistance: a report from the Drug-Resistant Streptococcus pneumoniae Therapeutic Working Group. Arch Intern Med 2000; 160:1399–1408. Bartlett JG, Dowell SF, Mandell LA, File TM Jr, Musher DM, Fine MJ. Practice guidelines for the management of community-acquired pneumonia in adults. Infectious Diseases Society of America. Clin Infect Dis 2000; 31:347–382. Niederman MS, Mandell LA, Anzueto A, et al. Guidelines for the management of adults with community-acquired pneumonia. Diagnosis, assessment of severity, antimicrobial therapy, and prevention. Am J Respir Crit Care Med 2001; 163:1730–1754. Fine MJ, Auble TE, Yealy DM, et al. A prediction rule to identify low-risk patients with community-acquired pneumonia. N Engl J Med 1997; 336:243– 250. Fine MJ, Stone RA, Singer DE, et al. Processes and outcomes of care for patients with community-acquired pneumonia: results from the Pneumonia Patient Outcomes Research Team (PORT) cohort study. Arch Intern Med 1999; 159:970–980. Marston BJ, Plouﬀe JF, File TMJr., et al. Incidence of community-acquired pneumonia requiring hospitalization. Results of a population-based active surveillance Study in Ohio. The Community-Based Pneumonia Incidence Study Group. Arch Intern Med 1997; 157:1709–1718. Doern GV, Brueggemann AB, Blocker M, et al. Clonal relationships among high-level penicillin-resistant Streptococcus pneumoniae in the United States. Clin Infect Dis 1998; 27:757–761. Chen DK, McGeer A, de Azavedo JC, Low DE. Decreased susceptibility of Streptococcus pneumoniae to ﬂuoroquinolones in Canada. Canadian Bacterial Surveillance Network. N Engl J Med 1999; 341:233–239.

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38. Rahav G, Toledano Y, Engelhard D, Simhon A, Moses A, Sacks T, Shapiro M. Invasive pneumococcal infections. A comparison between adults and children. Medicine (Baltimore) 1997; 76(4):295–303. 39. Plouﬀe JF, Breiman RF, Facklam RR. Bacteremia with Streptococcus pneumoniae. Implications for therapy and prevention. JAMA 1996; 275(3):194–198. 40. Friedland IR. Comparison of the response to antimicrobial therapy of penicillinresistant and penicillin-susceptible pneumococcal disease. Pediatr Infect Dis J 1995; 14(10):885–890. 41. Metlay JP, Hofmann J, Cetron MS, et al. Impact of penicillin susceptibility on medical outcomes for adult patients with bacteremic pneumococcal pneumonia. Clin Infec Dis 2000; 30:520–528. 42. Ewig S, Ruiz M, Torres A, et al. Pneumonia acquired in the community through drug-resistant Streptococcus pneumoniae. Am J Respir Crit Care Med 1999; 159:1835–1842. 43. Nightingale CH, Mattoes HM. Macrolide, azelide and ketolide pharmacodynamics. In: Nightingale CH, Murakawa T, Ambrose PG, eds. Antimicrobial Pharmacodynamics in Theory and Clinical Practice. New York: Marcel Dekker, 1999:205–220.

5 Treatment of Community-Acquired Respiratory Tract Infections with Ketolides Paul B. Iannini Danbury Hospital, Danbury and Yale University School of Medicine New Haven, Connecticut, U.S.A.

INTRODUCTION The ketolides are a new class of antibacterial agents derived from the 14membered macrolactone ring that characterizes the macrolides. Novel structural modiﬁcations result in enhanced binding to bacterial ribosomes through tighter binding at domain V of bacterial rRNA relative to erythromycin A and direct binding at a second site in domain II of bacterial rRNA. The result of this improved ribosomal binding is increased potency against respiratory tract pathogens, including macrolide-resistant strains. Ketolides do not induce expression of macrolide-lincosamide-streptograminB (MLSB) resistance. They have an optimum spectrum of activity for the treatment of respiratory tract infections (RTIs), being highly active against common, atypical, and intracellular respiratory pathogens such as Streptococcus pneumoniae (including penicillin-, macrolide-, and azalide-resistant strains), Haemophilus inﬂuenzae and Moraxella catarrhalis (including h-lactamase–producing strains), Staphylococcus aureus, Streptococcus pyogenes (including many macrolide- and azalide-resistant strains), respiratory anaerobes, Legionella 75

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Iannini

pneumophila, Chlamydophila pneumoniae, and Mycoplasma pneumoniae. Ketolides also possess good activity against Coxiella burnetii, Francisella tularensis, Corynebacterium diphtheriae, Bordetella pertussis, and Bordetella parapertussis. The ketolides display concentration-dependent bactericidal activity. They achieve high concentrations in plasma, respiratory tissues, alveolar macrophages, and neutrophils. Their targeted spectrum of antibacterial activity and favorable pharmacokinetic/pharmacodynamic (PK/PD) proﬁle make this class of agents ideal for the treatment of lower and upper RTIs, including community-acquired pneumonia (CAP), acute exacerbations of chronic bronchitis (AECB), acute maxillary sinusitis (AMS), and tonsillitis/pharyngitis. Telithromycin—the ﬁrst ketolide antibacterial to be approved for clinical use—has been both eﬀective and well tolerated in over 1 million patients since its commercial introduction. Telithromycin retains clinical eﬃcacy in the therapy of patients with resistant pathogens, and has been eﬃcacious even in the setting of bacteremic pneumococcal disease caused by penicillin- and macrolide-resistant strains. Side eﬀects, when they do occur, are mild and consistent in incidence and severity with other approved antibacterial agents, particularly the macrolides. Drug-drug interactions are few and are similar to those of the macrolides. KETOLIDE STRUCTURE The ketolides are structurally related to the 14-membered ring macrolides but a keto group replaces the L-cladinose at position 3 of the macrolactone ring [1] (Fig. 1). Replacement of the a L-cladinose sugar with a keto function avoids the induction of MLSB resistance [2]. Ketolides also contain a methoxy group at position 6 of the macrolactone ring that, in conjunction with the 3-keto group, improves stability in acidic environments by preventing internal hemiketalization. The L-cladinose moiety at position 3 of the macrolactone ring was previously thought to be essential for the antibacterial activity of macrolides, but it is now known that derivatizing other positions of the macrolactone ring can provide the same activity. In most developmental ketolides, a C11, C12-carbamate group is present and more than compensates for the removal of the L-cladinose group (Fig. 2). Telithromycin also possesses an aryl alkyl side chain extension to the C11, C12-carbamate (Fig. 2) [3]. The mode of action of the ketolides is similar to that of the macrolides. Both antibacterial classes bind to the 50S subunit of bacterial ribosomes and prevent bacterial protein synthesis by preventing mRNA translation and ribosomal assembly. Both macrolides and ketolides bind to domain V of the 23S rRNA. Due to the C11, C12-carbamate group, ketolides, unlike the macrolides, bind directly to a second site in domain II of the 23S rRNA of the 50S ribosomal subunit [4,5]. The secondary structure of bacterial 23S rRNA

Treatment of CRTIs with Ketolides

77

FIGURE 1 Macrolides and their derivatives. (From Ref. 2.)

showing the sites of interaction of the macrolides and ketolides is shown in Figure 3. There are two main mechanisms by which streptococci become resistant to macrolide antibacterials: target-site modiﬁcation (encoded by the erm genes) and drug eﬄux (encoded by the mef genes). Methylation of the adenine 2058 residue in domain V of bacterial rRNA causes MLSB phenotypic resistance to macrolides such as erythromycin A and clarithromycin, azalides such as azithromycin, lincosamides such as clindamycin, and Group B streptogramins such as quinupristin. Folding of the 23S ribosomal subunit brings domains II and V very near to each other at the junction of the peptide exit channel and adjacent to the petidyl transferase center. Ketolides retain activity against strains that have become MLSB resistant through methylation of adenine residue 2058 in domain V through their second interaction with adenine residue 752 in domain II of bacterial rRNA [6]. Ketolides do not elicit MLSB phenotypic expression of inducible erm genes and, thus far, have not caused selection of resistant strains [7]. Telithromycin is a poor substrate for

78

FIGURE 2 Macrolide/ketolide structure. (From Ref. 3.)

Iannini

Treatment of CRTIs with Ketolides

79

FIGURE 3 Bacterial 23S rRNA secondary structure showing the sites of interaction of the macrolides and ketolides. (From Ref. 3.)

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the mef eﬄux pump of S. pneumoniae and so is not aﬀected by this resistance mechanism. Telithromycin is also active against ribosomal protein L4 mutations in S. pneumoniae that confer resistance to macrolides and azalides [8]. Telithromycin binds wild-type ribosomes with 10-fold greater aﬃnity than erythromycin A and six-fold greater aﬃnity than clarithromycin, but its aﬃnity for MLSB-resistant ribosomes is more than 20 times greater than either macrolide [1]. Two ﬂuoroketolides (HMR 3562 and HMR 3787) that have a ﬂuoride atom in position 2 of the lactam ring are also under evaluation and may have increased potency against respiratory pathogens compared with their nonﬂuorinated ketolide derivatives [9]. GENERAL CLASS ASPECTS The ketolides have an optimal spectrum of antibacterial activity for the treatment of community-acquired RTIs. All of the common bacterial species involved in these infections are susceptible to ketolides, including strains of S. pneumoniae resistant to macrolides and azalides (including both mef and erm genotypes), h-lactams, and ﬂuoroquinolones. Ketolides are active against H. inﬂuenzae and M. catarrhalis (including h-lactamase–producing strains), S. aureus, oral anaerobes, atypical pathogens such as M. pneumoniae, and intracellular pathogens such as L. pneumophila and C. pneumoniae. h-Hemolytic group A streptococci (GABHS; S. pyogenes) are also susceptible, including many macrolide-resistant strains, particularly those with mef(A) or erm(A) subclass erm(TR) genotypes. Ketolides demonstrate concentrationdependent bactericidal activity against S. pneumoniae, and achieve high concentrations in respiratory tissues and serum. There is moderate cytochrome P450 metabolism and active drug is excreted by the kidneys and, to some extent, the liver. Drug-drug interactions are few and are similar to those of the macrolides. The targeted spectrum of activity of the ketolides makes these compounds attractive candidates for the treatment of community-acquired RTIs including CAP, AECB, AMS, and tonsillitis/pharyngitis, particularly in the current era of increasing bacterial resistance. TELITHROMYCIN Antibacterial Activity Telithromycin has potent activity against common, atypical, and intracellular respiratory pathogens, including strains that are resistant to h-lactam, MLSB, and ﬂuoroquinolone antibacterial agents (Table 1) [10, 11]. Telithromycin is more potent in vitro and in vivo against gram-positive cocci than clarithromycin or azithromycin. It is also highly active against inducible erm- (MLSB)

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TABLE 1 In vitro Susceptibility of Respiratory Tract Pathogens to Telithromycin Minimum inhibitory concentration (MIC; mg/L) Organism Streptococcus pneumoniae All Penicillin resistant Macrolide resistant Fluoroquinolone resistant Streptococcus pyogenes All Macrolide resistant Haemophilus influenzae All h-lactamase producing Moraxella catarrhalis All h-lactamase producing Chlamydophila pneumoniae Legionella pneumophila Mycoplasma pneumoniae

MIC50

MIC90

0.015 0.06 0.06 0.03

0.125 0.125 0.5 0.125

0.015 0.25

0.015 8

1 1

2 2

0.06 0.06 0.03 0.015 V0.015

0.06 0.125 0.06 0.03 V0.015

Penicillin (penicillin G resistant; intermediate plus resistant), minimum inhibitory concentration (MIC) z0.12 mg/L; macrolide (erythromycin A) resistant, MIC z1 mg/L; ﬂuoroquinolone (levoﬂoxacin) resistant, MIC z8 mg/L. Source: Refs. 10 and 11.

or mef-mediated macrolide-resistant strains of S. pneumoniae, S. pyogenes, and S. aureus, and constitutive erm (MLSB)-resistant strains of S. pneumoniae [12]. The activity of telithromycin against isolates of S. pneumoniae and S. pyogenes is superior to that of the respiratory quinolones such as levoﬂoxacin. The mode minimum inhibitory concentration (MIC) for S. pneumoniae is 0.008 mg/L, with an MIC90 of 0.125 mg/L. The MIC90 is essentially unchanged in penicillin-intermediate (MIC = 0.12 mg/L) or resistant (MIC z2 mg/L) strains (Table 1) [12, 13]. The MIC90 for erythromycin A-resistant strains of S. pneumoniae is moderately higher than that for susceptible strains (0.5 mg/L vs 0.015 mg/L, respectively) [14]. Telithromycin provides uniform bactericidal activity, with 99.9% killing after 24 hours and 99.0% killing at 12 hours at two times the MIC against both erythromycin A–sensitive and –resistant strains. Comparable activity for erythromycin A, clarithromycin, and azithromycin is achieved only in erythromycin A-susceptible strains [14].

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Similar results for telithromycin were obtained by the same investigators with time-kill curves for penicillin-susceptible and -resistant strains of S. pneumoniae. Telithromycin is also active against ﬂuoroquinolone-resistant strains of S. pneumoniae, with an MIC90 of 0.125 mg/L, regardless of the mechanism of resistance (either eﬄux or topoisomerase target mutation) [15]. Postantibiotic eﬀects of telithromycin for erythromycin A–susceptible gram-positive cocci are optimal: S. pneumoniae, 9.7 hr; S. pyogenes, 8.9 hr; S. aureus, 3.7 hr; only slightly shorter in erythromycin A-resistant strains [16]. The MIC90 for GABHS is 0.015 mg/L, compared with 0.12 mg/L for clarithromycin and 0.5 mg/L for azithromycin [15]. A large proportion of erythromycin A–resistant strains remains susceptible to telithromycin, with 98.5% of strains being inhibited at less than 0.5 mg/L [17]. Telithromycin’s activity against H. inﬂuenzae is signiﬁcantly greater than erythromycin A and clarithromycin, and similar to that of azithromycin, with an MIC range of 0.12–8.0 mg/L and an MIC90 of 2–4 mg/L (Table 1) [10,11,13]. The MIC90 of telithromycin for H. inﬂuenzae is unaﬀected by h-lactamase production [18]. Telithromycin has concentration-dependent bactericidal activity against H. inﬂuenzae over the initial 4 hr at concentrations equal to or above its MIC [18]. Telithromycin levels attained in pulmonary tissues and epithelial lining ﬂuid exceed these MICs. Telithromycin also possesses potent activity against isolates of M. catarrhalis, with an MIC90 of 0.06 mg/L, which is essentially unaﬀected by h-lactamase production (Table 1) [13]. Telithromycin possesses excellent activity against atypical/intracellular respiratory pathogens (Table 1). Telithromycin is highly active against C. pneumoniae with an MIC range of 0.015–0.0625 mg/L [19]; others have found an MIC range of 0.031–0.25 mg/L [18]. Telithromycin has bactericidal activity and signiﬁcant sub-MIC eﬀects against this intracellular pathogen [20,21]. Telithromycin is also highly active against L. pneumophila in vitro and in a guinea pig infection model [22], being more potent than erythromycin A against this pathogen [23]. M. pneumoniae is also extremely susceptible to telithromycin [24]. Telithromycin’s activity against gram-positive and -negative anaerobes is excellent and superior to that of macrolides and azalides [25]. Telithromycin is also more potent than macrolides against B. pertussis and has equal potency against B. parapertussis [26]. Telithromycin is bactericidal against intracellular F. tularensis [27], is more active against C. diphtheriae than macrolides and azalides [28], and is more active than erythromycin A against C. burnetii [29]. The activity of telithromycin has been compared with various macrolides, azithromycin, and pristinamycin using in vivo mouse infection models (including systemic infection and thigh muscle infection models). Telithro-

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mycin was found to be one of the most potent agents tested, being particularly eﬀective in protecting against systemic infection caused by macrolide-resistant pathogens and the most eﬀective compound against H. inﬂuenzae [30]. Pharmacokinetics and Pharmacodynamics The PK parameters of telithromycin in healthy volunteers following single and repeated once-daily oral doses of 800 mg are shown in Table 2. Steadystate plasma concentrations are achieved after 2–3 days with repeated dosing and slight accumulation occurs at 7–10 days, with an accumulation ratio of 1.2–1.5. The Cmax is dose proportional; the AUC0-24h increases threefold with a twofold increase in dose [31,32]. Telithromycin is 57% bioavailable and this is not aﬀected by food [33]. In clinical studies involving patients with RTIs, the Cmax was moderately higher than in healthy volunteers at 2.89 mg/L [34]. In the elderly, Cmax is 3.0–3.6 mg/L with an AUC0-24h of 11.56–17.17 mg.h/L and Tmax is shortened to <1 hr [35]. The terminal elimination half-life (t1/2, Ez) is 9.81 hr in healthy volunteers following multiple doses and renal clearance is 12.5 L/hr [35]. Renal clearance is moderately lower in the elderly, with an accumulation ratio of 1.45. At 800 mg, there are no diﬀerences between those with mild or moderate renal impairment and healthy volunteers [5]. In persons with severe renal impairment, there is a 1.4-fold increase in Cmax and a 1.9-fold increase in AUC0-24h [35]. Hepatic impairment of a moderate to severe degree reduces Cmax by 20% but AUC is not aﬀected [36]. Elimination of telithromycin is reduced in patients with hepatic impairment but does not lead to signiﬁcant accumulation due to an increase in renal excretion [36]. A large study of the PK proﬁle of more than 200 patients with CAP showed no signiﬁcant diﬀerences due to age, sex, body size, or renal function [37].

TABLE 2 Pharmacokinetic Parameters of Telithromycin in Healthy Volunteers after Single and Multiple 800 mg Doses Mean (%CV) Parameter Cmax (mg/L) tmax (h) AUC0-24h t1/2, Ez (h) a

Single dose

Multiple dosea

1.90 (42) 1.0 (0.5-4.0)b 8.25 (31) 7.16 (19)

2.27 (31) 1.0 (0.5–3.0)b 12.5 (43) 9.81 (20)

Once daily dosing for 7 days. Median (range). Source: Refs. 31 and 32.

b

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TABLE 3 Site to Serum Concentrations of Telithromycin after 800 mg Once-Daily Oral Dosing for 5–10 days Site

Healthy volunteers

Patients

55.0–540.0 ND 4.8–14.3 ND 101.0–2201.0

40.9–2159.6 2.1–12.1 8.6–14.4 3.4–13.1 ND

Alveolar macrophagesa Bronchial mucosaa Epithelial lining fluida Tonsillar tissuea White blood cellsb Abbreviation: ND, not determined. a 5-day telithromycin. b 10-day telithromycin. Source: Refs. 38 through 42.

Telithromycin concentrations in oropharyngeal and bronchopulmonary tissues are above the MICs for most key respiratory pathogens for a full 24 hr (38–41). Tissue-to-plasma ratios for respiratory and inﬂammatory cells and tissues are high [38–41] (Tables 3 and 4). Saliva to plasma ratios at Cmax are 1.2–1.5 and at Cmin are 3–5, with an AUC0-24 h of 1.7 mg.h/L. Telithromycin is avidly taken up by neutrophils and is concentrated 300-fold in azurophilic granules compared with plasma [42]. Fusion of telithromycinladen azurophilic granules with bacteria contained in phagosomes ensures high local intracellular drug levels [43]. In human volunteer studies with cantharidin-induced skin blisters, the blister ﬂuid concentration of telithromycin is 0.44 mg/L 9 hr after a single oral dose of 600 mg, with a plasma AUC0-24h ratio of 1.38 [44]. After oral administration of telithromycin, approximately 90% of the dose is absorbed. Prior to entering the systemic circulation, telithromycin undergoes a ﬁrst-pass eﬀect (33% of dose) due to presystemic metabolism mainly by the liver, but to some extent by the intestine. After reaching sys-

TABLE 4

AUC/MIC90 Ratios for Common Pathogens in CAP and

AECB AUC/MIC90 Pathogen S. pneumoniae H. influenzae M. catarrhalis S. aureus

CAP 12.5/0.03 12.5/4 12.5/0.12 12.5/0.12

= = = =

AECB 416.7 3.1 104.2 104.2

12.5/0.03 12.5/4 12.5/0.12 12.5/0.5

= = = =

416.7 3.1 104.2 25.0

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temic circulation (absolute bioavailability = 57%), telithromycin is eliminated via multiple pathways with 7% excreted unchanged in the feces by biliary and/or intestinal excretion, 13% excreted unchanged by the kidney and 37% metabolized by the liver. The metabolism is mediated by both the hepatic cytochrome P450 (CYP) system (mainly 3A4) and the non-CYP system [35,45]. Telithromycin exists in ﬁve forms in the circulating plasma, the majority (57%) of which is an unchanged form. Lesser amounts exist as N-desmethyl-desosamine, N-oxide-pyridine derivatives, an alcohol, and an acid [45]. Therapeutic Uses Telithromycin at a dosage of 800 mg once daily is approved for clinical use in the treatment of RTIs, based on clinical studies of CAP, AECB, and AMS in patients 18 years and older, and for tonsillitis/pharyngitis in patients 12 years and older. Community-Acquired Pneumonia Telithromycin 800 mg once daily for the recommended treatment duration of 7–10 days was evaluated in patients with CAP across six Phase III clinical studies (three open-label and three comparator-controlled studies vs clarithromycin 500 mg twice daily for 10 days, amoxicillin 1000 mg three-times daily for 10 days, or trovaﬂoxacin 200 mg twice daily for 7–10 days). Telithromycin was clinically eﬀective in 92.4% (1046/1132) and 91.0% (356/391) of patients in pooled and comparator-controlled studies, respectively, and clinical cure rates for telithromycin were equivalent to those of pooled comparators (90.4% [356/394]) [46,47]. Clinical cure rates were high for the major causative pathogens of CAP: 94.8% for S. pneumoniae, 90.5% for H. inﬂuenzae, and 86.7% for M. catarrhalis (Table 5) [35,48,49]. The clinical cure rate for patients with CAP caused by penicillin G– and/or erythromycin A– resistant S. pneumoniae (single- and mixed-pathogen infections) was 87.0% (Table 5) [48]. Clinical cure rates remained high in patients with risk factors for morbidity and mortality, including elderly patients (65 years and over; 90.3% [139/154]); patients with pneumococcal bacteremia (91.5% [43/47]); patients with a Fine score of III or over (92.0% [161/175]); and patients with infections caused by the atypical/intracellular pathogens C. pneumoniae, M. pneumoniae, and L. pneumophila (94.1% [32/34], 96.8% [30/31], and 100% [12/12], respectively) [50,51]. Acute Exacerbations of Chronic Bronchitis Telithromycin 800 mg once daily for 5 days is the recommended dosing regimen for the treatment of AECB. Clinical cure rates following 5-day telithro-

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TABLE 5 Clinical and Bacteriologic Cure Rates by Pathogen in Patients with Community-Acquired Pneumonia Who Were Treated with Telithromycin 800 mg Once Daily for 7–10 days Pathogen S. pneumoniae All PEN-R ERY-R PEN-R and/or ERY-R H. influenzae M. catarrhalis S. aureus Other All pathogens

Clinical cure, n/N (%) 165/174 13/16 13/16 20/23 95/105 26/30 15/19 102/114 403/442

(94.8) (81.3) (81.3) (87.0) (90.5) (86.7) (78.9) (89.5) (91.2)

Bacteriologic cure, n/N (%) 165/174 13/16 13/16 20/23 94/105 27/30 15/19 98/114 400/442

(94.8) (81.3) (81.3) (87.0) (89.5) (90.0) (78.9) (86.0) (90.5)

Abbreviations: PEN-R, penicillin G-resistant (minimum inhibitory concentration [MIC] z2 mg/L); ERY-R, erythromycin A-resistant (MIC z1 mg/L). Source: Refs. 35, 48, and 49.

mycin therapy compared favorably with those of a 10-day course of comparator antibacterials (cefuroxime axetil 500 mg twice daily or amoxicillinclavulanate 500/125 mg three-times daily). The overall clinical and bacteriologic cure rates for telithromycin were 86.3% [220/255] and 71.9% [46/ 64], respectively, and were similar to those of pooled comparators (82.7% [210/254] and 74.1% [43/58], respectively) [35,52]. Clinical cure rates for telithromycin remained high in elderly patients (87.8% [79/90]), in patients with one or more and two or more risk factors for morbidity (86.5% [128/148] and 84.3 [59/70], respectively), and in patients with severe bronchial obstruction (forced expiratory volume in 1 sec/forced vital capacity less than 60%; 82.4% [56/68]) [35,52]. Clinical and bacteriologic cure rates for telithromycin were similar to those of comparators at the late post-therapy visit (Table 6). The relapse rate at late post-therapy was low for telithromycin-treated patients and similar to the rates of comparator-treated patients (Table 6). Acute Maxillary Sinusitis Treatment with telithromycin 800 mg once daily for 5 or 10 days was compared with a 10-day course of comparator antibacterials (amoxicillin-clavulanate 500/125 mg three-times daily or cefuroxime axetil 250 mg twice daily) in patients with acute maxillary sinusitis. Clinical and bacteriologic cure rates following telithromycin therapy for 5 days (83.6% [383/458] and 87.6% [155/ 177]), respectively were equivalent to those of 10-day course of telithromycin (81.7% [223/273] and 89.5% [68/76], respectively) and a 10-day course of

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TABLE 6 Late Post-Therapy Clinical and Bacteriologic Cure Rates and Relapse Rates in Patients with Acute Exacerbations of Chronic Bronchitis Who Were Treated with Telithromycin or a Comparator Antibacterial Therapeutic regimen Telithromycin 800 mg once daily, 5 days Amoxicillin/clavulanate 500/125 mg three-times daily, 10 days Cefuroxime axetil 500 mg twice daily, 10 days

Clinical cure, n/N (%)

Bacteriologic cure, n/N (%)

Relapse, n/N (%)

185/236 (78.4)

38/58 (65.5)

16/236 (6.8)

81/108 (75.0)

16/26 (61.5)

7/108 (6.5)

104/136 (76.5)

18/27 (66.7)

8/136 (5.9)

Source: Ref. 35.

comparator antibacterials (77.4% [175/226] and 78.9% [45/57], respectively) [35,53]. Clinical cure rates by pathogen for 5- and 10-day telithromycin are shown in Table 7. Five-day telithromycin therapy retained high clinical cure rates in at-risk patients including those with severe infection (86.3% [82/95]), those with total sinus opacity (88.4% [153/173]), and patients with allergic rhinitis (81.3% [61/75]) [35,53]. A 5-day course of telithromycin is currently recommended for the treatment of AMS.

TABLE 7 Clinical Cure Rates by Pathogen in Patients with Acute Maxillary Sinusitis Who Were Treated with Telithromycin 800 mg Once Daily for 5 or 10 Days Clinical cure, n/N (%) Pathogen S. pneumoniae All PEN-R and/or ERY-R H. influenzae M. catarrhalis S. aureus S. pyogenes Other All pathogens

5-day telithromycin 55/61 14/16 42/48 13/14 18/19 2/2 62/81 192/225

(90.2) (87.5) (87.5) (92.9) (94.7) (100) (76.5) (85.3)

10-day telithromycin 27/30 6/7 15/16 3/4 4/4 3/3 38/42 90/99

(90.0) (85.7) (93.8) (75.0) (100) (100) (90.5) (90.9)

Abbreviations: PEN-R, penicillin G-resistant (minimum inhibitory concentration [MIC] z2 mg/ L); ERY-R, erythromycin A-resistant (MIC z1 mg/L). Source: Refs. 35 and 53.

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Tonsillitis/Pharyngitis Telithromycin 800 mg once daily for 5 days has been evaluated in the therapy of tonsillitis/pharyngitis caused by GABHS (S. pyogenes) in adults and adolescents. Telithromycin achieved clinical and bacteriologic cure rates of 93.6% (248/265) and 88.3% (234/265), respectively, which were equivalent to the rates of 92.5% (235/254) and 88.6% (225/254), respectively, achieved with a 10-day course of comparator antibacterials (clarithromycin 250 mg twice daily or phenoxymethylpenicillin 500 mg three-times daily) [54–57]. S. pyogenes eradication rates were similar in telithromycin-, penicillin-, and clarithromycin-treated patients (Table 8) [54–56]. Five-day telithromycin therapy is currently recommended for the treatment of GABHS tonsillitis/ pharyngitis. Safety and Tolerability The safety and tolerability of telithromycin have been investigated across nine comparator-controlled Phase III clinical studies (telithromycin, n=2045; comparators, n=1672). Telithromycin was consistently well tolerated. Adverse events, when they did occur, were of mild to moderate intensity, and less than 4% of telithromycin-treated patients discontinued therapy due to adverse events considered possibly related to treatment—a rate that was similar to that for comparator antibacterials (Table 9) [35]. Gastrointestinal adverse events such as diarrhea, nausea, and vomiting were the most frequently reported adverse events considered possibly related to treatment, although dizziness was also reported (Table 9) [35]. The majority of discontinuations in both the telithromycin and comparator treatment groups were due to possibly treatment-related adverse events of the gastrointestinal system (diarrhea, nausea, and vomiting). The safety proﬁle of telithromycin was similar across patient age groups, with elderly (z65 years) and adolescent patients (13–18 years) experiencing adverse events with a similar frequency and intensity to adult patients (>13–<65 years) [35]. TABLE 8 Streptococcus pyogenes Eradication Rates in Patients with GABHS Pharyngitis Tonsillitis Who Were Treated with Telithromycin or a Comparator Antibacterial Therapeutic regimen Telithromycin 800 mg once daily, 5 days Penicillin V 500 mg three-times daily, 10 days Clarithromycin 250 mg twice daily, 10 days Source: Refs. 54 through 56.

Eradication rate, n/N (%) 235/265 (88.7) 106/119 (89.1) 120/135 (88.9)

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TABLE 9 Incidence of Treatment-Related Adverse Events in Patients Receiving Telithromycin or a Comparator Antibacterial for the Treatment of Respiratory Tract Infections Patients, n (%) Telithromycin (n=2045) Adverse events All adverse events All GI events Diarrhea Nausea Vomiting Dizziness

712 495 272 166 57 73

(34.8) (24.2) (13.3) (8.1) (2.8) (3.6)

Discontinuations 76 56 19 18 19 5

(3.7) (2.7) (0.9) (0.9) (0.9) (0.2)

Pooled comparators (n=1672) Adverse events 465 246 158 64 24 26

(27.8) (14.7) (9.5) (3.8) (1.4) (1.6)

Discontinuations 51 28 13 9 6 1

(3.1) (1.7) (0.8) (0.5) (0.4) (0.1)

Abbreviation: GI, gastrointestinal. Source: Ref. 35.

The eﬀect of telithromycin on QTc interval was very small (mean QTc increase of approximately 1 msec) and similar to that of clarithromycin [35]. The incidence of arrhythmia and cardiovascular adverse events was low for telithromycin and similar to that for comparator antibacterials (0.2% [3/ 1793] and 2.6% [47/1793], respectively, vs. 0.1% [2/1537] and 3.0% [46/1537], respectively) [35]. The incidence of clinically noteworthy abnormal laboratory values (abnormal hematology and clinical chemistry) was low and similar for telithromycin- and comparator-treated patients [36]. Telithromycin is a competitive inhibitor of CYP3A4 and, like the macrolides, may produce increases in plasma levels of drugs that are metabolized by this isoenzyme such as simvastatin, midazolam, and cisapride. Coadministration of potent CYP 3A4 inhibitors such as ketoconazole and itraconazole may lead to moderate increases in telithromycin exposure [35]. REFERENCES 1. 2.

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Iannini HMR 3647 and seven other antimicrobial agents against Corynebacterium diphtheriae. J Antimicrob Chemother 2001; 47:27–31. Rolain JM, Maurin M, Bryskier A, Raoult D. In vitro activities of telithromycin HMR3647) against Rickettsia rickettsii, Rickettsia conorii, Rickettsia africae, Rickettsia typhi, Rickettsia prowazekii, Coxiella burnetii, Bartonella henselae, Bartonella quintana, Bartonella bacilliformis, and Ehrlichia chaﬀeensis. Antimicrob Agents Chemother 2000; 44:1391–1393. Bonnefoy A, Guitton M, Delachaume C, LePriol P, Girard A. In vivo eﬃcacy of the new ketolide telithromycin (HMR 3647) in murine infection models. Antimicrob Agents Chemother 2001; 45:1688–1692. Namour F, Wessels DH, Pascual MH, Reynolds D, Sultan E, Lenfant B. Pharmacokinetics of the new ketolide telithromycin (HMR 3647) administered in ascending single and multiple doses. Antimicrob Agents Chemother 2001; 45:170–175. Lenfant B, Sultan E, Wable C, Pascual MH, Meyer BH, Scholtz. Pharmacokinetics of 800 mg once-daily oral dosing of the ketolide, HMR 3647, in healthy young volunteers (Abstract A-49). Abstracts of the 38th Interscience Conference on Antimicrobial Agents and Chemotherapy. Washington DC: American Society for Microbiology, 1998. Perret C, Wessels DH. Oral bioavailability of the ketolide telithromycin (HMR 3647) is similar in both elderly and young subjects. Clin Microbiol Infect 2000; 6(suppl 1):203–204. Sultan E, Lenfant B, Wable C, Pascual M-H, Meyer B. Pharmacokinetic proﬁle of HMR 3647 800mg once-daily in elderly volunteers. J Antimicrob Chemother 1999; 44(suppl A):54. Brieﬁng document for the FDA Anti-infective Drug Products Advisory Committee Meeting. Aventis, Bridgewater, NJ, USA, March 2001. Sultan E, Cantalloube C, Patat A, Moirand R. Telithromycin (HMR 3647), the ﬁrst ketolide antimicrobial, does not require dosage adjustment in individuals with hepatic impairment. Clin Microbiol Infect 2000; 6(suppl 1):203. Pluim J. Population pharmacokinetics support the convenient once-daily 800 mg dosage of telithromycin in patients with upper and lower RTIs including special populations. Clin Microbiol Infect 2001; 7(suppl 1):266. Gehanno P, Passot V, Nabet P, Sultan E. Telithromycin (HMR 3647) penetrates rapidly into tonsillar tissue achieving high and prolonged tonsillar concentrations. Clin Microbiol Infect 2000; 6(suppl 1):204. Muller-Serieys C, Cantalloube C, Soler P, Ghia HP, Brunner F. HMR 3647 achieves high and sustained concentrations in broncho-pulmonary tissues. J Antimicrob Chemother 1999; 44(suppl A):57. Kadota J, Ishimatsu Y, Iwashita T, Matsubara Y, Kohno S, Tateno M, et al. The ketolide antimicrobial telithromycin (HMR 3647) achieves high and sustained concentrations in alveolar macrophages and bronchoalveolar epithelial lining ﬂuid in healthy Japanese volunteers (Abstract 2142). Abstracts of the 40th Interscience Conference on Antimicrobial agents and Chemotherapy. Washington DC: American Society for Microbiology, 2000.

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41. Khair OA, Andrews JM, Honeybourne D, Jevons G, Vacheron F, Wise R. Lung concentrations of telithromycin after oral dosing. J Antimicrob Chemother 2001; 47:837–840. 42. Pham Gia H, Roeder V, Namour F, Sultan E, Lenfant B. HMR 3647 achieves high and sustained concentrations in white blood cells in man. J Antimicrob Chemother 1999; 44(suppl A):57–58. 43. Miossec-Bartoli C, Pilatre L, Peyron P, N’Diaye EN, Collart-Dutilleul V, Maridonneau-Parinin I, et al. The new ketolide HMR 3647 accumulates in the azurophilic granules of human polymorphonuclear cells. Antimicrob Agents Chemother 1999; 43:2457–2462. 44. Namour F, Sultan E, Pascual MH, Lenfant B. Penetration of telithromycin (HMR 3647), a new ketolide antimicrobial, into inﬂammatory blister ﬂuid following oral administration. J Antimicrob Chemother 2002; 49:1035–1038. 45. Sultan E, Namour F, Mauriac C, Lenfant B, Scholtz H, et al. HMR 3647, a new ketolide antimicrobial, is metabolized and excreted mainly in feces in man. J Antimicrob Chemother 1999; 44(suppl A):54. 46. van Rensburg D, Rangaraju M, Jenkins S, Pluim J. Telithromycin provides high clinical and bacteriologic eﬃcacy in patients with community-acquired pneumonia irrespective or gender or age (Abstract 62.013). In: Abstracts of the 10th International Congress on Infectious Diseases. Singapore: Society of Infectious Diseases (Singapore) and the Singapore Society for Microbiology and Biotechnology, 2002. 47. van Rensburg D, Moola S, Hagberg L, Rangaraju M, Leroy B. Oral telithromycin is as eﬀective as standard comparators for the treatment of communityacquired pneumonia (Abstract 862). In: Abstracts of the 41st Interscience Conference on Antimicrobial Agents and Chemotherapy. Washington DC: American Society for Microbiology, 2001. 48. Hagberg L, Rangaraju M, Jenkins S. Eﬃcacy of telithromycin in the treatment of community-acquired pneumonia caused by resistant pneumococci. Clin Microbiol Infect 2002; 8(suppl 1):318. 49. van Rensburg D, Rangaraju M, Jenkins S, Pluim J. Clinical and bacteriologic eﬃcacy of telithromycin in patients with community-acquired pneumonia caused by Haemophilus inﬂuenzae (Abstract 62.014). In: Abstracts of the 10th International Congress on Infectious Diseases. Singapore: Society of Infectious Diseases (Singapore) and the Singapore Society for Microbiology and Biotechnology, 2002. 50. Rangaraju M, Leroy B, Pluim J. Telithromycin is eﬀective in the treatment of high-risk patients with community-acquired pneumonia (Abstract 08.02). In: Program and Abstracts of the 6th International Conference on the Macrolides, Azalides, Streptogramins, Ketolides and Oxazolidinones. Atlanta, GA: ICMAS Inc. and the Sixth International Conference on the Macrolides, Azalides, Streptogramins, Ketolides and Oxazolidinones, 2002. 51. Dunbar L, Hagberg L, Rangaraju M, Leroy B. Seven to 10-day therapy with telithromycin, the ﬁrst ketolide antimicrobial, is eﬀective in community-acquired pneumonia caused by atypical and intracellular pathogens (Abstract 859). In:

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6 Treatment of Community-Acquired Respiratory Tract Infections with Quinolone Antibacterial Agents Vincent T. Andriole Yale University School of Medicine New Haven, Connecticut, U.S.A.

Paul G. Ambrose Cognigen Corporation Buffalo, New York, U.S.A.

Robert C. Owens, Jr. Maine Medical Center Portland, Maine, U.S.A.

QUINOLONES: A BRIEF HISTORY AND CHEMISTRY OVERVIEW The dawn of modern antibacterial chemotherapy began in the 1930s when Germany’s Gerhard Domagk identiﬁed sulfonamides as chemotherapeutic agents, for which he was awarded the Nobel prize in medicine in 1938 [1]. The development of penicillin G, by England’s Sir William Dunn and Australia’s Howard Florey, followed during the early 1940s [2]. Tetracycline (chlortetracycline, 1948), aminoglycoside (streptomycin, 1949), macrolide (erythromy95

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cin, 1952), and glycopeptide (vancomycin, 1956) antibacterial classes were introduced during the decade that followed the end of World War II [3]. The development of quinolone antibacterial agents began in the early 1960s. Nalidixic acid (Fig. 1B), chemically a naphthyridine, was serendipitously discovered during chloroquine synthesis in 1962 [4]. Due to its reliable activity against most Enterobactereaceae, for a time nalidixic acid became a popular choice for the treatment of uncomplicated urinary tract infections. In fact, early on it was often referred to as an oral therapeutic equivalent of kanamycin. Unfortunately, its serum and tissue concentrations were so low that it could not be employed for infections in other body sites. Moreover, its half-life was so short, nalidixic acid had to be given four times daily. Several other similar quinolones (e.g., oxolinic acid and cinoxacin) were developed

FIGURE 1 Structures of representative quinolones.

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that were essentially identical with nalidixic acid but could be given less frequently. None of these ﬁrst-generation quinolones exhibited any activity against Pseudomonas aeruginosa, anaerobes, or gram-positive bacteria. Norﬂoxacin, the ﬁrst second-generation quinolone, expanded quinolone bacterial coverage to include P. aeruginosa and staphylococci. This change was the result of the discovery that placement of a ﬂuorine at the C-6 position of the 4-quinolone molecule and replacement of the C-7 methyl side chain of nalidixic acid with a piperazine group signiﬁcantly enhanced microbiological activity (Fig. 1C) [5–7]. Generally, second-generation quinolones have a spectrum of microbiological activity similar to that of the aminoglycosides. Replacement of norﬂoxacin’s N-1 ethyl group with a cyclopropyl group resulted in compounds with greater bioavailability, such as ciproﬂoxacin (Fig. 1D) [5–7]. Due to the summation of the C-6, C-7, and N-1 structural changes, compounds such as ciproﬂoxacin and oﬂoxacin can be used in many sites of infection outside of the urinary tract. Moreover, these quinolones exhibit high intracellular penetration, allowing for the treatment of atypical organisms, such as Chlamydia spp., Mycoplasma spp., and Legionella spp. [8]. Norﬂoxacin is available as an oral formulation and is useful only for the treatment of urinary tract infections. Like norﬂoxacin, lomeﬂoxacin and enoxacin are available only as oral formulations but may be used for a limited number of systemic infection sites. Ciproﬂoxacin and oﬂoxacin are available in both intravenous and oral formulations and are useful in treating many systemic sites of infection. Unfortunately, none of the second-generation quinolones exhibit adequate pharmacokinetic/pharmacodynamic (PK-PD) proﬁles against Streptococcus pneumoniae and/or have suﬃcient clinical outcome data to be used reliably to treat serious infections caused by these organisms. Although, for a short time there was a quinolone, temaﬂoxacin, with appreciable pneumococcal activity, it had to be withdrawn from the market due to the emergence of a syndrome of hemolysis and renal dysfunction [9]. This represented a serious problem for the clinician, because the leading cause of communityacquired pulmonary and sinus infection is S. pneumoniae, and the major cause of pharyngitis, soft tissue infections, and skin infections is S. pyogenes. This opened the door for the development of third-generation quinolones (sparﬂoxacin, grepaﬂoxacin). These agents have moderate PK-PD proﬁles and in vitro microbiological activity against S. pneumoniae. Forth-generation quinolones (garenoxacin, gatiﬂoxacin, gemiﬂoxacin, moxiﬂoxacin, trovaﬂoxacin, sitaﬂoxacin) are characterized as having signiﬁcantly improved PK-PD proﬁles against S. pneumoniae compared with levoﬂoxacin. Moreover, these agents also have appreciable activity against anaerobes, such as Bacteroides fragilus. The enhanced streptococcal activity

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of these compounds results from modiﬁcations to the piperazine group at C-7 of the quinolone nucleus [7]. The addition of a sterically bulky group(s) on this substituent not only improved the PK-PD proﬁle of these agents against gram-positive organisms but also diminished the potential for adverse CNS events and drug interactions (Fig. 1E,F). The enhanced activity against anaerobes arise from either bulky substituents attached to the C-8 position of the 4-quinolone nucleus or N-8 substitutions of the 4-quinolone nucleus itself. While the C-8 methoxy group of moxiﬂoxacin and gatiﬂoxacin (Fig. 1E,F) and the sterically bulky group of garenoxacin confer moderate activity against many anaerobic species, an N-8 substitution (trovaﬂoxacin) provides for superior anaerobic activity (Fig. 1G) [7,10,11].

PHARMACOKINETIC-PHARMACODYNAMIC PROPERTIES OF QUINOLONES Pharmacokinetics-Pharmacodynamics: First Principles Harry Eagle, a half-century ago, pioneered the ﬁrst pharmacokinetic-pharmacodynamic (PK-PD) studies using penicillin in streptococcal and syphilitic animal models of infection [12–14]. It was at this time that dosing methods (e.g., continuous infusion vs. intermittent injection) as well as the dose of penicillin employed in relation to the minimum inhibitory concentration (MIC), were evaluated for its ability to impact in vivo outcome. Following a long respite, the science now known as PK-PD reemerged as Shah and colleagues classiﬁed antimicrobial agents based on their patterns of bactericidal activity [15]. Two patterns of bactericidal activity were described, time-dependent and concentration-dependent (Fig. 2). The rate of bacterial killing exhibited by time-dependent agents is saturable over a narrow range of drug concentrations and usually reaches a plateau when drug concentrations are approximately 2–4 times the MIC of the pathogen to the drug [16]. (Fig. 2) h-Lactams (e.g., penicillins, cephalosporins, monobactams, carbapenems), lincosamides (e.g., clindamycin), macrolides (e.g., erythromycin, clarithromycin), and oxazolidinones (e.g., linezolid) best ﬁt this pattern of bactericidal activity. Thus, the duration of time (T) that drug concentrations exceed some threshold (such as the MIC) would be predicted to be the PK parameter that determines in vivo eﬃcacy [17]. On the other hand, the rate and extent of bacterial killing exhibited by concentration-dependent agents is saturable over a much broader range of drug concentrations, usually 10–20 times the MIC of the drug to the pathogen [16] (Fig. 2). In other words, as drug concentration increases, so does

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FIGURE 2 Time-kill curves of Pseudomonas aeruginosa with exposure to tobramycin, ciprofloxacin, and ticarcillin at concentrations ranging from one-fourth to 64 times the MIC. Tobramycin and ciprofloxacin exhibit a concentrationdependent pattern of bactericidal activity, whereas ticarcillin exhibits a concentration-independent pattern of bactericidal activity. (From Ref. 17.)

the rate of bacterial killing. Agents that demonstrate this pattern of bactericidal activity include the aminoglycosides, quinolones, daptomycin, vancomycin, teicoplanin, oritavancin, amphotericin B, and telithromycin. Thus, the peak drug concentration and the area under the serum concentrationtime curve at 24 hours (AUC24) would be predicted to be the PK parameters that determine in vivo eﬃcacy [17]. Pharmacokinetic parameters determining eﬃcacy may be transformed to PK-PD measures by indexing PK to a measure of drug potency, such as the MIC. More speciﬁcally, from a PK standpoint, bacterial killing can be characterized mathematically. Bacterial killing may be described by the integral of drug concentration (C) over time ( mCdt) or the AUC. Hence, from a PK-PD perspective, bacterial killing is a function of a drug’s AUC when indexed to the MIC. Under certain circumstances, changes in either concentration or time will make a small or negligible contribution to the killing process. In these instances, the PK-PD measure can be simpliﬁed to the peak concentration (peak):MIC ratio or time the serum concentration remains above the MIC (T > MIC). When one of these simplifying assumptions cannot be made, the eﬃcacy of most antimicrobial agents can usually be linked to the AUC24: MIC ratio [16].

a

Dual elimination pathways exist.

Site of infection

Enterobacteriaceae + Atypicals P. aeruginosa

Microbiological activity

Ofloxacin (Floxin) Levofloxacin (Levaquin) Ciprofloxacina (Cipro)

Urine +/ Systemic

Enterobacteriaceae + P. aeruginosa

Enterobacteriaceae

Urine only

Norfloxacin (Noroxin) Enoxacin (Penetrex) Lomefloxacin (Maxaquin)

Second

Quinolone Generations (PK-PD Classiﬁcation)

Nalidixic acid Oxolinic acid Cinoxacin

First

TABLE 1

Systemic +/ Urine

Enterobacteriaceae P. aeruginosa (+/) Atypicals + S. pneumoniae

Sparfloxacin (Zygam) Grepafloxacina (Raxar)

a

Third

Systemic +/ Urine

Enterobacteriaceae P. aeruginosa (+/) Atypicals S. pneumoniae + Anaerobes

Trovafloxacina (Trovan) Gatifloxacin (Tequin) Moxifloxacina (Avelox) Gemifloxacina (Factive) Garenoxacin (BMS 284756) Sitafloxacin (DU 6859a)

Fourth

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Identiﬁcation of the primary PK-PD measure that determines eﬃcacy is complicated by the high degree of colinearity between measures. For instance, a larger dose of a given drug results not only in a larger peak:MIC ratio but also in a larger AUC24:MIC ratio and a longer T>MIC. Because all three PK-PD measures increase with ascending dose, it can be diﬃcult to determine which measure is most closely associated with any increase in eﬃcacy. One way to overcome this colinearity is by comparng the eﬀects of several total doses administered over various intervals (i.e., dose fractionation studies). In this way, one may identify the PK-PD measure that is most important to in vivo eﬃcacy [17]. Pharmacokinetic-Pharmacodynamic Target Thresholds For quinolones, like other agents that exhibit concentration-dependent bactericidal activity, bacterial killing is maximized when the free-drug ( f ) AUC24:MIC ratio or the f peak:MIC ratio exceed a target threshold. It appears that the optimal PK-PD targets are pathogen- and patient population– speciﬁc. Generally, the PK-PD measure that best correlates with eﬃcacy of quinolones is the CAUC24:MIC ratio. Whereas the f peak:MIC ratio has been shown to be important in vitro and in vivo in the prevention of the emergence of quinolone-resistant mutants. In the following discussion we will explore quinolone PK-PD data derived from nonclinical models of infection (in vitro and animal) as well as that from clinical studies. Quinolones are classiﬁed based on their pharmacodynamic proﬁle (Table 1). PK-PD Target Thresholds and Gram-Negative Bacilli Leggett et al. published the earliest study evaluating the PK-PD of quinolones against gram-negative bacilli in 1991. The study evaluated ciproﬂoxacin in neutropenic murine thigh and pulmonary infection models using strains of P. aeruginosa and Klebsiella pneumoniae [18]. Dose fractionation in these studies minimally impacted the extent of bacterial killing, suggesting that the CAUC24:MIC ratio was the PK-PD measure most closely associated with eﬃcacy. Since that time, it has become well established in animal models of infection involving gram-negative bacilli, where the change in bacterial density (D log10 CFU) after 24 hours of therapy is used as the endpoint, CAUC24:MIC ratios of approximately 50 are associated with a net bacteriostatic eﬀect (i.e., no net change in log10 CFU), and ratios of 100 are associated with a 1 to 2 log-unit reduction (i.e., a 90–99% reduction in bacterial density). Similarly, in animal models of infection involving gram-negative bacilli, where mortality is used as the endpoint, about 50% and 90% animal survival is associated with CAUC24:MIC ratios of approximately 50 and 100, respectively. The magnitude of the CAUC24:MIC ratio associated with these

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endpoints have been consistent irrespective of dosing regimen, site of infection, or the quinolone studied [17]. Some of the ﬁrst data to correlate PK-PD and response in humans were published by Peloquin and colleagues [19]. Intravenous ciproﬂoxacin was evaluated in the treatment of lower respiratory tract infections involving predominantly gram-negative bacilli in seriously ill patients hospitalized in the intensive care unit. A relationship between time of exposure and outcome was established. Interestingly, against P. aeruginosa, a low peak:MIC ratio (<10:1) was observed that resulted in the development of resistance in 10 of 13 pathogens. Although the authors concluded that the time of exposure was the important determinant of outcome against diﬃcult-to-treat and less susceptible pathogens (e.g., P. aeruginosa), failure to obtain an optimal peak:MIC ratio resulted in the emergence of resistance. This is consistent with ﬁndings from the animal model of infection reported by Drusano, further emphasizing the importance of peak:MIC ratio when dealing with resistant subpopulations [20]. Eventually, after the addition of 24 new patients, Forrest and colleagues in 1993 published their reanalyzed data from the 1989 publication (Fig. 3) [21]. After the authors performed a multivariate analysis

FIGURE 3 Relationship between the AUC24:MIC ratio (total drug) and the probability (%) of clinical and microbiological response to therapy for ciprofloxacin against gram-negative bacilli in seriously ill patients. (From Ref. 21.)

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and logistic regression, the AUC24:MIC ratio predicted outcome best–not the time of exposure that was previously reported. PK-PD Target Thresholds and Gram-Positive Cocci As mentioned earlier, the optimal PK-PD targets are pathogen-and patient population–speciﬁc. Several recently published or presented studies have evaluated the PK-PD relationships of quinolones against gram-positive pathogens, particularly pneumococci. For S. pneumoniae, in vitro models of infection have demonstrated that for ciproﬂoxacin, garenoxacin, gatiﬂoxacin, levoﬂoxacin, moxiﬂoxacin, and sparﬂoxacin, CAUC24:MIC ratios of approximately 30 or greater are associated with a four log-unit reduction in bacterial density; lesser CAUC24:MIC ratios are often associated with a signiﬁcantly reduced extent of bacterial killing and in some instances bacterial regrowth (Fig. 4) [22–25]. Studies in animal models of infection identiﬁed a similar PK-PD target threshold. Onyeji and colleagues compared the eﬃcacy of ciproﬂoxacin and levoﬂoxacin in a murine model of peritoneal sepsis [26]. Clinical isolates of S. pneumoniae were used that displayed a range of susceptibilities to penicillin; MIC values for ciproﬂoxacin (1 and 2 Ag/mL) and levoﬂoxacin (1 and 2 Ag/ mL) were reﬂective of that seen clinically. Dosing regimens were varied in a

FIGURE 4 PK-PD time-kill curves of garenoxacin against S. pneumoniae. Each line represents changes in bacterial density over time for a single experiment; the numbers at the right side of each line represent the f AUC:MIC ratio for that experiment. f AUC:MIC ratios of 29 or greater resulted in the elimination of S. pneumoniae from the model, whereas lesser ratios did not. (Courtesy of Philip Lister.)

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manner that resulted in drug exposures similar to those achieved in humans. Survival diﬀerences between ciproﬂoxacin and levoﬂoxacin groups were negligible (P > 0.05), perhaps because the AUC24:MIC ratios were not that diﬀerent from those seen in humans. For ciproﬂoxacin, AUC24:MIC ratios were between 17.5 and 35; and for levoﬂoxacin, between 22 and 44. Neither ciproﬂoxacin nor levoﬂoxacin achieved a desirable peak:MIC ratio of at least 10. Further, Craig and Andes studied six quinolones in the mouse-thigh infection model in an eﬀort to determine optimal CAUC24:MIC ratios in terms of survival and change in bacterial density [27]. After being infected with S. pneumoniae, mice were treated with ciproﬂoxacin, gatiﬂoxacin, gemiﬂoxacin, levoﬂoxacin, moxiﬂoxacin, or sitaﬂoxacin. The authors found that the fAUC:MIC ratio best predicted animal survival after 96 hr of therapy and the change in log10 CFU after 24 hr of therapy. CAUC24:MIC ratios of 25 to 34 or greater were associated with approximately 90% animal survival and a 2 to 2.5 log-unit reduction in bacterial density (Fig. 5). Preston and colleagues evaluated the association between diﬀerent PKPD measures for levoﬂoxacin and both clinical and microbiological outcomes [28]. In this study, concentrations of levoﬂoxacin in serum were obtained after administration of standard doses appropriate for site of infection in patients being treated for urinary tract, pulmonary, and skin/soft tissue infections. Of the initial 313 patients, 116 had suﬃcient pharmacokinetic, microbiological and clinical outcome data for evaluation. Patients in whom a peak:MIC ratio greater than 12.2 was achieved had a 100% chance of having the infecting organism eradicated from the site of infection. Conversely, if the peak:MIC ratio was less than 12.2, the likelihood of successful eradication was 80.8%. Although there was signiﬁcant colinearity between the PK-PD measures of peak:MIC and AUC24:MIC ratio on outcome predictability, the peak:MIC ratio reached a higher level of statistical signiﬁcance for all pathogens and infection sites. A recent reanalysis of the infections caused by S. pneumoniae, however, revealed that CAUC24:MIC ratios greater than 30 were associated with positive outcome [29]. These data are consistent with the previous work conducted by Drusano et al., which demonstrated that when a peak:MIC ratio of at least 10:1 could not be achieved, the PK-PD measure most closely associated with outcome is the AUC24:MIC ratio. Most recently, Ambrose et al. evaluated the relationship between the CAUC24:MIC ratio of gatiﬂoxacin and levoﬂoxacin against S. pneumoniae and the microbiological response of patients enrolled in phase III, doubleblinded, randomized trials conducted in North America [30]. Of the 778 patients enrolled in these studies involving either community-acquired pneumonia or acute bacterial exacerbation of chronic bronchitis, 376 patients had suﬃcient clinical and microbiological data for evaluation. Of these pa-

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FIGURE 5 Relationship between f AUC24:MIC ratio and survival (A) and change in bacterial density (B) for six quinolones (ciprofloxacin, gatifloxacin, gemifloxacin, levofloxacin, moxifloxacin, or sitafloxacin). (Courtesy of William A. Craig.)

tients, 58 were infected with S. pneumoniae that was isolated from either blood or sputa. These data established that for gatiﬂoxacin and levoﬂoxacin, CAUC24:MIC ratio of at least 33.7 correlated with the eradication of S. pneumoniae in patients being treated for pneumococcal pulmonary infections (Fig. 6). CAUC24:MIC ratios greater than 33.7 were associated with patients having a 100% positive microbiological response to therapy, while those patients with CAUC24:MIC ratio less than 33.7 had only a 64% response to therapy.

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Figure 6 Relationship between the AUC24:MIC ratio (free drug) and the probability (%) of microbiological response to therapy for gatifloxacin and levofloxacin against Streptococcus pneumoniae in patients with community-acquired respiratory tract infections. (From Ref. 27.)

PK-PD Target Thresholds and the Prevention of Resistance Although there are considerably fewer data available, it is likely that a relationship also exists between the AUC24:MIC and peak:MIC ratios and the development of resistance. Drusano and coworkers evaluated lomeﬂoxacin in the neutropenic rat model of pseudomonas sepsis [20]. Doses were administered in a variety of regimens to study the eﬀect of diﬀerent PK-PD measures associated with outcome. The peak:MIC ratio was signiﬁcantly associated with reduced mortality, compared with AUC24:MIC ratio and the time over MIC. The doses used in this study provided peak:MIC ratios of approximately 20:1 and less than 10:1. The clear association between peak: MIC ratio and survival was postulated to be due to the increased inoculum size used (109) in the study. These ﬁndings demonstrated that with a higher burden of organisms, one is more likely to encounter resistant sub-populations, and in such settings the peak:MIC ratio becomes the more appropriate PK-PD measure that best predicts outcome. Thomas and coworkers described this relationship in 107 hospitalized patients being treated for bacterial pneumonia [31]. Patients received a variety of dosing regimens of ciproﬂoxacin (200 mg q12h to 400 mg q8h) or a cephalosporin (cefmenoxime, 1–2 g q4–6hr or ceftazidime, 1–2 g q8–12hr), providing a wide range of exposures. Gram-negative pathogens predominated, as expected among patients with nosocomial pneumonia, accounting for over 90% of the organisms isolated. Gram-positive pathogens, such as S. aureus and S. pneumoniae, were isolated in less than 10% of cases. With the exception

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of Bush group 1 h-lactamase–elaborating organisms (e.g., Enterobactor spp.) treated with a h-lactam, PK-PD breakpoints were established. If a AUC24: MIC ratio of at least 100 was achieved, the potential to develop resistance was less than 10%. In contrast, the probability of developing a resistant strain during therapy was greater than 80% if the AUC24:MIC ratio was less than 100. Because the majority of pathogens encountered were gram-negative bacilli (most of which being P. aeruginosa), it is diﬃcult to generalize these ﬁndings to gram-positive pathogens. Many more data are needed to further understand the relationship between PK-PD measures and the development of resistance. Pharmacokinetics, Microbiology, and Toxicity Pharmacokinetics The pharmacokinetic proﬁles for the newer and some older quinolones are listed in Table 2. Due to intravenous-oral bioequivalence, quinolones have revolutionized the treatment of many infectious diseases. Whether quinolones are administered intravenously or orally, similar PK-PD relationships can be achieved with most quinolones because of their high degree of bioavailability that is consistent among the newer-generation agents. Protein binding is one characteristic that is highly variable among the quinolones. The degree of protein binding not only inﬂuences penetration into tissues but also determines the amount of drug that is capable of interacting with bacteria at the site of infection [32]. The exact role of protein binding is often more controversial than not, but clearly, the pharmacokinetic parameter used in pharmacodynamic analyses should reﬂect free drug (active drug) rather than total drug concentrations. Microbiology The majority of community-acquired respiratory tract infections are most usually associated with one or more of six microbiologic etiologies. These include extracellular pathogens, such as S. pneumoniae, H. inﬂuenzae, and M. catarrhalis and intracellular pathogens such as Legionella spp. , Mycoplasma pneumoniae, and Chlamydia pneumoniae. Quinolones, such as garenoxacin, gatiﬂoxacin, levoﬂoxacin, and moxiﬂoxacin, have appreciable in vitro activity against both the extracellular and intracellular pathogens commonly associated with community-acquired respiratory tract infections. With regard to gram-positive microorganisms such as S. pneumoniae, garenoxacin and the 8-methoxy quinolones (gatiﬂoxacin and moxiﬂoxacin) are markedly more active than ciproﬂoxacin, oﬂoxacin, or levoﬂoxacin. It is important to note that the activity of quinolones against S. pneumoniae is unrelated to penicillin resistance. The rank order of in vitro

750 70 25 3.5 2.6 64 48 4 60

11.6 3.3 40

Ciprofloxacin

400 50 15 1.5 1.3 13.6

Norfloxacin

6 95

33.3

500 99 30 6 4.2 47.5

Levofloxacin

20 10

10.6

200 92 40 1.3 0.8 17.7

Sparfloxacin

9 85

41.0

400 96 20 4.3 3.4 51.3

Gatifloxacin

Overview of Pharmacokinetic Properties of Selected Quinolones

Dose (mg) Bioavailability (%) % Protein bound Peak (Ag/mL) Free Peak (Ag/mL) AUC(0–24) (Ag .h/mL) Free AUC(0–24) (Ag .h/mL) T1/2 (hr) % Renal elim. (active drug)

Parameter

TABLE 2

12 20

21.6

400 90 55 4.5 2.0 48

Moxifloxacin

12 6

7.8

200 88 75 2.3 0.6 31.2

Trovafloxacin

7.4 30

3.8

320 80 59 1.48 0.6 9.3

Gemifloxacin

108 Andriole et al.

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activity of quinolones against S. pneumoniae is garenoxacin ! moxiﬂoxacin ! gatiﬂoxacin ! levoﬂoxacin ! ciproﬂoxacin = oﬂoxacin. Against staphylococci, moxiﬂoxacin = gatiﬂoxacin ! garenoxacin ! levoﬂoxacin ! levoﬂoxacin = oﬂoxacin. Third- and fourth-generation quinolones have excellent in vitro activity against gram-negative respiratory pathogens such as H. inﬂuenzae and M. catarrhalis. Moreover, these agents have in vitro activity against most Enterobacteriaceae, such as Citrobactor spp., Enterobactor spp., Escherichia coli, and Klebsiella pneumoniae. Finally, all third- and fourth-generation quinolones are highly active against Legionella spp. The newer agents (garenoxacin, gatiﬂoxacin, and moxiﬂoxacin), however, are more active against M. pneumoniae and C. pneumoniae than ciproﬂoxacin, levoﬂoxacin, and oﬂoxacin. Toxicities Associated with Quinolones Phototoxicity. Phototoxicity is a dramatic dermatological complication of quinolone therapy that usually occurs within hours of exposure to ultraviolet (UV) light, with reactions ranging in severity from mild to severe. Phototoxicity has been observed with all known quinolones [33]. These reactions are most commonly associated with speciﬁc agents, particularly lomeﬂoxacin, sparﬂoxacin, and clinaﬂoxacin and are related to chemical structure. Compounds with a halogen (CL or F) at the 8-position of the quinolone nucleus have the most phototoxic potential [6]. Quinolones with an 8-methoxy group (gatiﬂoxacin and moxiﬂoxacin) have the least potential for phototoxicity [34]. The overall phototoxic potential of quinolones is lomeﬂoxacin, ﬂeroxacin ! sparﬂoxacin, clinaﬂoxacin ! enoxacin ! peﬂoxacin ! grepaﬂoxacin, ciproﬂoxacin ! norﬂoxacin, oﬂoxacin, levoﬂoxacin, trovaﬂoxacin ! gatiﬂoxacin, moxiﬂoxacin. Central Nervous System. Seizures are rare and usually involve patients with central nervous system disorders such as epilepsy or patients who are also receiving NSAIDs or theophylline [33]. The exact mechanism by which quinolones induce seizures is controversial. There appears to be a strong association with similarities of structure for certain substituents at the 7position of the quinolone nucleus and the structure of the gamma-aminobutyric acid (GABA) [35]. Some quinolones appear to displace or compete with GABA binding at receptor sites within the CNS, resulting in CNS stimulation. Several researchers have demonstrated associations between 7piperazine– (ciproﬂoxacin, enoxacin, norﬂoxacin) and 7-pyrolidine– (tosuﬂoxacin, clinaﬂoxacin) containing quinolones and increased epileptic potential. Methyl-substituted 7-piperazinyl- or 7-pyrolidine- compounds (gatiﬂoxacin, levoﬂoxacin, and sparﬂoxacin) are associated with a reduction in epileptic

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potential. In general, quinolones should be used with caution in those patients who have a history of a seizure disorder or who are also receiving potentially epileptogenic medications. Severe Idiosyncratic and Immune-Mediated Reactions. Triﬂuorinated quinolones (temaﬂoxacin, tosuﬂoxacin, ﬂeroxacin, trovaﬂoxacin) may pose greater risks of certain serious toxicities, the most serious being a hepato-renal syndrome (e.g., temaﬂoxacin syndrome) characterized by serious hemolysis and often a new-onset renal and/or hepatic dysfunction (57% and 51% of cases, resepectively) [9]. The high frequency of adverse events associated with ﬂeroxacin (84% with 48% being classiﬁed as severe, in a study of 79 patients), has been suggested to be related to triﬂourination [36,37]. Tosuﬂoxacin was associated with eosinophilic pneumonitis in a study in Japan, where it is available for clinical use [38]. Trovaﬂoxacin hepatic-related injury was also associated with eosinophilic inﬁltration. Genotoxicity. Quinolones exert their activity by inhibiting bacterial DNA gyrase (topoisomerase II) and topoisomerase IV. Because mammalian cells also contain DNA gyrases, the possibility exists that quinolones may disrupt chromosomes in humans, a process known as clastogenicity. Position1, -7, and -8 govern genotoxicity in humans. Groups associated with increased cytotoxicity potential include position-1 (cyclopropyl, tertiary butyl, 2,4 diﬂuorophenyl) and position-8 (Cl, F, methoxy). The exact nature of such toxicities in humans has not been well elucidated. Cardiotoxicity. Concerns about the cardiac safety of ﬂuoroquinolones emerged after the withdrawal of grepaﬂoxacin and sparﬂoxacin from the marketplace—owing, in part, to their potential to prolong the QTc interval, resulting in cardiac toxicity [39]. Fluoroquinolones were recently added to the growing list of antimicrobial agents that can cause delays in cardiac repolarization, leading to changes in the QTc interval manifested on the surface electrocardiogram (ECG). Macrolides, ketolides, azole antifungals, pentamidine, halofantrine, and very rarely trimethoprim/sulfamethoxazole are also associated with QTc prolongation [39]. The consequence of QTc prolongation is the establishment of an electrophysiological milieu that predisposes to the occurrence of cardiac arrhythmias, including torsades de pointes (TdP). The most common mechanism for drug-induced QTc prolongation is the blockade of the human ethera`-go-go related gene (HERG) that encodes the rapid delayed rectiﬁer potassium current (lkr) [40]. This leads to QTc interval prolongation because it results in accumulation of potassium within the myocyte that delays cardiac repolarization. This delayed repolarization can lead to early after-depolarizations, which, if repetitive and self-sustaining, can lead to TdP.

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The ‘‘multiple-hit hypothesis’’ suggests that multiple risk factors inﬂuence the development of TdP [41]. Risk factors include female gender; concurrent treatment with drugs also known to cause QTc interval prolongation, such as amiodarone and sotalol; metabolic drug interactions that result in signiﬁcantly elevated levels of a drug known to prolong the QTc interval; organ impairment that results in larger than usual drug exposures; electrolyte derangements (e.g., hypokalemia, hypomagnesemia); underlying comorbid diseases (e.g., congestive heart failure, atrial ﬁbrillation); bradycardia; and genetic polymorphisms (e.g., long QT syndrome) [39,42]. A case series of gatiﬂoxacin-associated TdP and ventricular arrhythmias demonstrates the multiple-hit hypothesis, as multiple risk factors were present in all four patients [43]. Also, if drugs that prolong the QTc interval are concurrently administered, they may have an additive eﬀect in blocking the lkr current, particularly if they are given with class Ia and class III antiarrhythmic agents (e.g., amiodarone, sotalol, dofetilide). Such combinations should be avoided. Spontaneous reports to the Food and Drug Administration (FDA) Adverse Event Reporting System can be used to characterize risk factors for TdP in large populations once the drug has been approved for use [44,45]. These studies indicate that the overall risk associated with ﬂuoroquinolones is very small. Levoﬂoxacin had the most cases reported (n = 14), and moxiﬂoxacin had the fewest (n = 3). Futhermore, large-scale post-marketing (phase IV) safety surveillance studies have been conducted for both gatiﬂoxacin and moxiﬂoxacin [46–48]. Results from a study of gatiﬂoxacin in 15,625 patients, including 4906 who had underlying cardiovascular disease or were receiving cardiovascular drugs, indicated no cardiovascular events related to gatiﬂoxacin [46]. Similarly, data from 7368 patients enrolled in clinical trials and 36,569 patients from safety surveillance studies indicated no signiﬁcant arrhythmic potential associated with moxiﬂoxacin [48]. In fact, in over 13 million patient exposures, four conﬁrmed cases of TdP and one unconﬁrmed case have been reported [48]. The risk of TdP in patients receiving ﬂuoroquinolones is very low. The concurrent use of gatiﬂoxacin, moxiﬂoxacin, or levoﬂoxacin with class Ia or class III antiarrhythmic agents must be avoided in all patients. Clinical Use of Quinolones Food and Drug Administration Approved Indications Ciproﬂoxacin. Ciproﬂoxacin is approved for use in pneumonia, acute exacerbation of chronic bronchitis, acute maxillary sinusitis, urinary tract infections including uncomplicated and complicated pyelonephritis, uncomplicated urogenital and rectal gonorrhea, chronic bacterial prostatitis,

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uncomplicated skin and soft tissue infections, bone and joint infections, infectious diarrhea, typhoid fever, intra-abdominal infection when used with metronidazole, Legionella infections, and febrile neutropenia. Gatiﬂoxacin. Gatiﬂoxacin is approved for use in community-acquired pneumonia, acute exacerbation of chronic bronchitis, acute maxillary sinusitis, urinary tract infections including uncomplicated and complicated pyelonephritis, uncomplicated urogenital gonorrhea, and uncomplicated skin and soft tissue infections. Additionally, gatiﬂoxacin is under FDA review for pediatric use for recurrent otitis media. Levoﬂoxacin. Levoﬂoxacin is approved for the following indications: community-acquired pneumonia, acute exacerbation of chronic bronchitis, acute maxillary sinusitis, nosocomial pneumonia, urinary tract infections including uncomplicated and complicated pyelonephritis, and uncomplicated skin and soft tissue infections. Moxiﬂoxacin. Moxiﬂoxacin is approved for use in communityacquired pneumonia, acute exacerbation of chronic bronchitis, acute maxillary sinusitis, and uncomplicated skin and soft tissue infections. Trovaﬂoxacin. Trovaﬂoxacin is indicated for the treatment of patients whose therapy is initiated in inpatient health care facilities who have serious life- or limb-threatening infections, including nosocomial pneumonia, community-acquired pneumonia, complicated intra-abdominal infection, gynecologic and pelvic infecions, and complicated skin and skin structure infections. Appropriate Use of Quinolones in Community-Acquired Respiratory Tract Infections Community-Acquired Pneumonia. Recommendations for empirical therapy for inpatients with community-acquired pneumonia include the combination of a h-lactam and a macrolide or a ﬂuoroquinolone alone [49]. Because ﬂuoroquinolones are highly eﬀective against the common extracellular (S. pneumoniae, Haemophilus inﬂuenzae, Moraxella catarrhalis) and atypical intracellular (M. pneumoniae, C. pneumoniae, Legionella spp.) respiratory pathogens, these agents oﬀer an excellent approach to the treatment of community-acquired pneumonia. Currently there are three quinolones available in the United States that are frequently used for the treatment of community-acquired pneumonia in both the in- and outpatient setting: gatiﬂoxacin, levoﬂoxacin, and moxiﬂoxacin. Of the approved quinolones, moxiﬂoxacin and gatiﬂoxacin have superior pharmacokinetic-pharmacodynamic (PK-PD) proﬁles against S. pneumoniae compared with that of levoﬂoxacin. A recent report for the

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Antimicrobial Resistance Rate Epidemiology Team (ARREST Program) systematically compared the in vitro susceptibility patterns and estimated the probability of attainment of the PK-PD target ratios for gatiﬂoxacin and levoﬂoxacin against pneumococci worldwide [50]. Monte Carlo simulation was used to estimate the probability that gatiﬂoxacin or levoﬂoxacin would achieve a CAUC24:MIC ratio of 30 or greater. The MIC at which 50% of isolates were inhibited (MIC50) and the MIC90 for North American isolates were 0.25 and 0.5 mg/liter, respectively, for gatiﬂoxacin, and 1 and 2 mg/liter, respectively, for levoﬂoxacin. The probabilities of attaining a CAUC24:MIC ratio greater than 30 for North American isolates were 97.6% for gatiﬂoxacin and 78.9% for levoﬂoxacin. Moreover, there are similar data available comparing moxiﬂoxacin or garenoxacin with levoﬂoxacin with similar results [51,52]. The results of these types of analyses in combination with accumulating data on the development of levoﬂoxacin resistance and subsequent treatment failure in pneumococcal pneumonia [53] suggest it may be the least attractive of the aforementioned quinolones for the treatment of community-acquired pneumonia. Acute Exacerbation of Chronic Bronchitis. Patients with chronic bronchitis typically suﬀer from several acute exacerbations each year that adversely aﬀect their quality of life and ability to function [54]. Acute exacerbations of chronic bronchitis are common and account for more than 10 million physician visits per year in the United States [55]. Approximately 50% of acute exacerbations of chronic bronchitis are bacterial in origin, and the predominant causative pathogens include S. pneumoniae, H. inﬂuenzae, and M. catarrhalis [56]. Routine treatment of acute exacerbations of chronic bronchitis is associated with failure or relapse rate of 17–32% [57]. Moreover, acute exacerbations of chronic bronchitis are a common cause of morbidity and mortality in sicker patients. Quinolones such as gatiﬂoxacin, levoﬂoxacin, and moxiﬂoxacin have proved to be safe and eﬀective in treating patients with acute bacterial exacerbations of chronic bronchitis. Recent studies have shown that patients treated with moxiﬂoxacin experience faster resolution of symptoms, fewer missed work hours, and higher work productivity than patients treated with early-generation quinolones, h-lactams, or macrolides [58]. Additionally, numerous studies have shown that bacteriological eradication rates are higher with quinolones compared with macrolide and h-lactam antimicrobial agents [59–62]. Acute Bacterial Maxillary Sinusitis. Diagnosis of patients with acute bacterial maxillary sinusitis involves the evaluation of various major and minor factors [63]. Major diagnostic factors include nasal congestion/ obstruction, nasal purulence/drainage, facial pressure/pain, hyposmia/anos-

400 mg 500 mg

500 mg

500 mg

Sinusitis CAP

ABECB

Sinusitis

400 mg 400 mg 400 mg

q24 hr q24 hr q24 hr

q24 hr

q24 hr

q24 hr q24 hr

q24 hr

q24 hr

q12 hr q12 hr q12 hr

Frequency

7–14 days 5 days 10 days

10–14 days

7 days

10 days 7–14 days

5 days

7–14 days

7–14 days 7–14 days 10 days

Length of therapy

No

Yes

Yes

Yes

Dose adjust for renal function

Hemodialysis & CAPD:

Crcl 10–19:

Crcl 20–49:

Hemodialysis & CAPD:

Crcl 30–50: Crcl 5–29: Hemodialysis & peritoneal dialysis: Crcl < 40mL/min:

Creatinine clearance

Initial dose: 500 mg Subsequent dose: 250 mg q24 hr Initial dose: 500 mg Subsequent dose: 250 mg q48 hr Initial dose: 500 mg Subsequent dose: 250 mg q48 hr

Initial dose: 400 mg Subsequent dose: 200 mg q24 hr Initial dose: 400 mg Subsequent dose: 200 mg q24 hr

250–500 mg q12 hr 250–500 mg q18 hr 250–500 mg q24 hr (after dialysis)

Dose and frequency

CAP = community-acquired pneumonia; ABECB = acute bacterial exacerbation of chronic bronchitis; Crcl = Creatinine clearance.

Moxifloxacin

CAP ABECB Sinusitis

400 mg

ABECB

Levofloxacin

400 mg

CAP

Gatifloxacin

500mg–750 mg 500 mg–750 mg 500 mg

CAP ABECB Sinusitis

Ciprofloxacin

Oral dose

Infection

Dosage regimen for renal dysfunction

FDA-Approved Dosing Regimens of Selected Quinolones for Community-Acquired Respiratory Tract Infections

Agent

TABLE 3

114 Andriole et al.

Treatment of CRTIs with Quinolones

115

mia, and fever; minor diagnostic factors include cough, ear pressure/fullness, fatigue, halitosis, headache, and dental pain. Diagnosis is based on the presence of two or more major factors, or one major and two minor factors and evidence of purulent nasal discharge on examination. The predominant causative pathogens include S. pneumoniae (20–43%), H. inﬂuenzae (22– 35%), M. catarrhalis (2–10%), and other streptococcal spp. (3–9%) [63]. Quinolones such as gatiﬂoxacin, levoﬂoxacin, and moxiﬂoxacin have proved safe and eﬀective in treating patients with acute bacterial rhinosinusitis. Recent studies have shown that 5-day treatment regimens of quinolones are as eﬀective as 10-day treatment courses of other drug classes. For instance, a recent three-arm study comparing gatiﬂoxacin 400 mg once daily for 5 days to gatiﬂoxacin 400 mg once daily for 10 days to amoxicillin-clavulanate 875 mg twice daily for 10 days found no statistical diﬀerence in clinical eﬃcacy between either of the three treatment groups [64]. Similarly, other studies have shown higher eﬃcacy rates with quinolones when compared with longer treatment courses of macrolide antimicrobial agents [65]. Appropriate Doses Food and Drug Administration–approved dosing recommendations for quinolones commonly used for the treatment of community-acquired respiratory tract infections are shown in Table 3.

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38. Kimura N, Miyazaki E, Matsuno O, et al. Drug-induced pneumonitis with eosinophilic inﬂitration due to tosuﬂoxacin tosilate. Nihon Kokyuki Gakkai Zasshi 1998; 36:618–622. 39. Owens RC Jr. Risk assessment for antimicrobial agent-induced QTc interval prolongation and torsades de pointes. Pharmacotherapy 2001; 21:301–319. 40. Kang J, Wang L, Chen X-L, Triggle DJ, Rampe D. Interactions of a series of ﬂuoroquinolone antibacterial drugs with the human cardiac K+ channel HERG. Mol Pharmacol 2001; 59:122–126. 41. Ruskin JN. Antibiotic cardiotoxicity [abstr]. In: Program and abstracts of the 41st Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, Illinois. Washington, DC: American Society for Microbiology, December 16–19, 2001:41. 42. De Ponti F, Poluzzi E, Cavalli A, Recanatini M, Montanaro N. Safety of nonantiarrhythmic drugs that prolong the QT interval or induce torsade de pointes. Drug Safety 2002; 25:263–286. 43. Bertino JS, Owens RC Jr, Carnes TD, Iannini PB. Gatiﬂoxacin-associated corrected QT interval prolongation, torsades de pointes, and ventricular ﬁbrillation in patients with known risk factors. Clin Infect Dis 2002; 34:861– 863. 44. Shaﬀer D, Singer S, Korvick J, Honig P. Concomitant risk factors in reports of torsades de pointes associated with macrolide use: Review of the United States Food and Drug Administration Adverse Event Reporting System. Clin Infect Dis 2002; 35:197–200. 45. Frothingham MD. Rates of torsades de pointes associated with ciproﬂoxacin, oﬂoxacin, levoﬂoxacin, gatiﬂoxacin, and moxiﬂoxacin. Pharmacotherapy 2001; 21:1468–1472. 46. Anriole VT. The quinolones; prospects. In: VT Andriole, ed. The Quinolones. 3d ed. Academic Press: San Diego, 47–495. 47. Iannini PB, von Seggern K, Wikler MA. Safety of gatiﬂoxacin in patients with cardiovascular disease [abstr]. In: Program and abstracts of the 40th Interscience Conference on Antimicrobial Agents and Chemotherapy, Toronto, Ontario, Canada. Washington, DC: American Society for Microbiology, September 17–20, 2000. 48. Iannini P, Kubin R, Reiter C. Over 10 million patient uses: An update on the safety proﬁle of oral moxiﬂoxacin. In: Program and abstracts of the 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, California. Washington, DC: American Society for Microbiology, September 27–30, 2002. 49. Gleason PP. The emerging role of atypical pathogens in community-acquired pneumonia. Pharmacotherapy 2002; 22:2S–11S. 50. Jones RN, Rubino CM, Bhavnani BM, Ambrose PG. Worldwide antimicrobial susceptibility patterns and pharmacodynamic comparisons of gatiﬂoxacin and levoﬂoxacin against Streptococcus pneumoniae: Report from the antimicrobial resistance rate epidemiology study team. Antimicrob Agents Chemother 2003; 47:292–296.

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51. Owens RC, Ambrose PG. Minimum eﬃcacy and mutation prevention exposure target attainment rates against Streptococcus pneumoniae for levoﬂoxacin 500 mg and 750 mg and moxiﬂoxacin 400 mg. In: Program and abstracts of the 40th Infectious Disease Society of America, Chicago, Illinois, October, 2002. 52. Ambrose PG, Jones RN, Gajjar DA, Van Wart S, Rubino CM, Bhavnani SM, Grasela DM. Use of Monte Carlo simulation to evaluate the antibacterial activity of garenoxacin against Gram-positive bacteria. In: Program and abstracts of the 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy. San Diego, California, September 27–30, 2002. 53. Davidson R, Cavalcanti R, Bruton JL, et al. Resistance to levoﬂoxacin and failure of treatment of pneumococcal pneumonia. N Engl J Med 2002; 346:747– 750. 54. Nicolson P, Anderson P. The patients’ burden: physical and psychological eﬀects of acute exacerbations of chronic bronchitis. J Antimicrob Chemother 2000; 45:25–32. 55. Niederman MS, McCombs JS, Unger AN, Kumar A, Popovian R. Treatment of acute exacerbations of chronic bronchitis. Clin Ther 1999; 21:576–591. 56. Sethi S. Infectious etiology of acute exacerbations of chronic bronchitis. Chest 2000; 117(suppl):380S–385S. 57. Adams SG, Anzueto A. Antibiotic therapy in acute exacerbations of chronic bronchitis. Semin Respir Infect 2000; 15:234–247. 58. Andriole CL, Andriole VT. Are all quinolones created equal? Mediguide Infect Dis 2002; 21:1–5. 59. Langan CE, Zuck P, Vogel F, et al. Randomized, double blind study of short course grepaﬂoxacin versus clarithromycin in patients with acute exacerbations of chronic bronchitis. J Antimicrob Ther 1999; 43:529–539. 60. Langan CE, Cranﬁeld R, Breisch S, Pettit R. Randomized, double blind study of grepaﬂoxacin versus amoxicillin in patients with acute exacerbations of chronic bronchitis. J Antimicrob Agents Chemother 1997; 40:63–72. 61. Shal PM, Maesen F, Colmann A, Vetter N, Fiss E, Wesch R. Levoﬂoxacin versus cefuroxime axetil in the treatment of acute exacerbations of chronic bronchitis: results of a randomized double blind study. J Antimicrob Chemother 1999; 43:529–539. 62. Wilson R, Kubin R, Ballin I, et al. Five day moxiﬂoxacin therapy compared with 7-day clarithromycin therapy for the treatment of acute exacerbations of chronic bronchitis. J Antimicrob Chemother 1999; 44:501–513. 63. Sinus and Allergy Health Partnership. Antimicrobial treatment guidelines for acute bacterial rhinosinusitis. Otolaryngol Head Neck Surg 2000; 123: S1–S38. 64. Sher LD, McAdoo MA, Bettis RB, Turner MA, Li NF, Pierce PF. A multicenter, randomized, investigator-blinded study of 5- and 10-day gatiﬂoxacin versus 10day amoxicillin/clavulanate in patients with acute bacterial sinusitis. Clin Ther 2002; 24:269–281. 65. Sher LD, Poole MD, Von Seggern K, Wikler MA, Nicholson SC, Pankey GA. Community-based treatment of acute uncomplicated bacterial rhinosinusitis with gatiﬂoxacin. Otolaryngol Head Neck Surg 2002; 127:182–189.

7 Treatment of Community-Acquired Respiratory Tract Infections with Penicillins and Cephalosporins Sandra L. Preston and George L. Drusano Albany Medical College Albany, New York, U.S.A.

Penicillins and cephalosporins belong to the h-lactam class of antimicrobials. Benzylpenicillin has been utilized since 1941 and cephalosporins began to be used clinically in the 1960s. Because of their spectrum of activity, the penicillins and cephalosporins have utility in treatment of communityacquired respiratory tract infections. This chapter will discuss the mechanism of action, pharmacokinetics, and pharmacodynamics of the penicillins and cephalosporins, as well as the utility of these drugs in the treatment of community-acquired respiratory tract infections. The number of h-lactams available for clinical use is extensive, so this chapter will limit discussion to the agents that are indicated and used clinically for treatment of communityacquired respiratory tract infections. STRUCTURE ACTIVITY RELATIONSHIPS The h-lactam agents have in common a basic structure, which includes the h-lactam ring. Penicillins have a thiazolidine ring and a side chain (Fig. 1). 121

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FIGURE 1 Penicillin structure. A-thiazolidine ring; B-beta-lactam ring; R1- acyl side chain.

Manipulations of the side chain can help to sterically protect the h-lactam ring from hydrolysis by h-lactamase, thereby enhancing the activity of some penicillins against organisms such as Staphylococcus aureus or gram-negative rods with speciﬁc types of h-lactamase. The side chain can also protect against gastric acid degradation and lead to increased permeability of the compound, thus enhancing the oral absorption [1]. Cephalosporins are characterized by a dihydrothiazine ring, a h-lactam ring, and variations on two side chains (R-1 or C-7 and R-2 or C-3) (Fig. 2). Substitutions at the R-1 side chain can confer increased activity against hlactamase–producing organisms by enhancing stability against some of these enzymes. The addition of a methoxy group at this position increases activity versus anaerobic bacteria, as seen with the cephamycins, cefoxitin and cefotetan. Substitutions at the R-2 side chain can extend the half-life of the drug, but the methylthiotetrazole (MTT) side chain at this position has been associated with hypoprothrombinemia and bleeding due to competitive inhibition of vitamin K–dependent clotting factors [2]. Drugs that contain this side chain at C3 are cefotetan, cefmetazole, cefomandole, and cefoperazone. MECHANISM OF ACTION The h-lactams are bactericidal drugs that inhibit bacterial cell wall synthesis by binding to enzymes called h-lactam (penicillin)-binding proteins (PBPs)

FIGURE 2 Cephalosporin structure. A-beta-lactam ring; B-dihydrothiazine ring; R1 and R2-positions for side chains.

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located beneath the cell wall of bacteria. This binding inhibits a main component of the cell wall, peptidoglycan cross-linkage, which weakens the cell wall [3,4]. Binding to diﬀerent PBPs can produce diﬀerent morphologic changes. This is best seen in the eﬀects on the morphology of gram-negative bacilli. The ability of the drug to penetrate the cell wall and, in gram-negative organisms, the outer membrane plus the ability to bind to the PBPs diﬀers among drugs. For instance, penicillin G does not penetrate the cell wall of many gram-negative organisms; therefore, there is limited activity against these organisms. Alterations in PBPs can lead to resistance as seen in penicillin-resistant Streptococcus pneumoniae. Interestingly, these changes are not driven by classical mutational mechanisms. Rather, pneumococci take in the altered PBP DNA of other oral streptococci that have become h-lactam resistant to produce mosaic chromosomes. Classically, these organisms have mutations in PBP 2b and PBP 2x. MECHANISMS OF RESISTANCE There are three main mechanisms of resistance for the h-lactams, including (1) enzymatic degradation of the h-lactam, (2) alteration of the PBP target site, and (3) decreased permeability of the drug through the outer membrane. This latter mechanism primarily involves gram-negative organisms and will not be the focus of this discussion. Enzymatic Degradation Production of h-lactamase can hydrolyze the h-lactam ring and lead to loss of antimicrobial activity of the drug. Both gram-positive and gram-negative organisms can produce h-lactamases. The most relevant organisms that produce h-lactamases in community-acquired respiratory tract infection are H. inﬂuenzae and M. catarrhalis. These gram-negative bacteria secrete hlactamases into the periplasmic space and hydrolyze the drug before it can acylate its target, the active site serine of the h-lactam binding proteins. Alteration in Penicillin-Binding Proteins (PBP) The primary mechanism of resistance of Streptococcus pneumoniae to hlactams is an alteration in the PBP after sequential chromosomally mediated mutations in several high-molecular-weight PBPs. These mutations lead to a decreased ability of the h-lactam to bind to the PBP [5]. Since not all h-lactams bind to the same PBPs, there may be diﬀerences in susceptibility between agents of the class. The mechanism of resistance is complex and involves gene transfer events from closely related commensal Streptococcus species, leading to the presence of mosaic genes [6].

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ANTIMICROBIAL ACTIVITY The most common community-acquired respiratory pathogens are Streptococcus pneumoniae, Haemophilus inﬂuenzae, Moraxella catarrhalis, and the atypical organisms, Mycoplasma pneumoniae, Legionella pneumophila, and Chlamydia pneumoniae. The penicillins are classiﬁed into diﬀerent groups according to antimicrobial spectrum characteristics and other similarities (Table 1). The natural penicillins, penicillin G and penicillin VK, have activity against Streptococcus pneumoniae. The aminopenicillins, ampicillin and amoxicillin, are drugs that have further manipulation of the side chain, and have enhanced activity against gram-negative organisms, speciﬁcally non–hlactamase producing Haemophilus inﬂuenzae. Because h-lactamase is commonly produced by H. inﬂuenzae isolates, the combination of a h-lactamase inhibitor, clavulanate, with amoxicillin (Augmentin), can inhibit the h-lactamases carried and allow these organisms to be killed by clinically achievable concentrations of amoxicillin. The penicillinase-resistant penicillins are active against Staphylococcus aureus and Staphylococcus epidermidis that produce penicillinase. The extended-spectrum penicillins include the carboxypenicillins (carbenicillin and ticarcillin), the ureidopenicillins (azlocillin and mezlocillin), and the piperazine penicillin (piperacillin). These agents have excellent coverage against gram-negative bacilli and anaerobes and are used primarily for nosocomial respiratory tract infection and other indications. The h-lactams are not active against the atypical pathogens or Staphylococcus unless accompanied by a hlactamase inhibitor. The cephalosporins are somewhat arbitrarily divided into four ‘‘generations’’ based on their spectrum of activity (Table 2). First-generation cephalosporins are active against gram-positive cocci, including penicillinaseTABLE 1

Classiﬁcation of Penicillins

Natural penicillins

Penicillinase-resistant

Aminopenicillins

Cloxacillin Dicloxacillin Nafcillin Oxacillin

Ampicillin Bacampicillin Amoxicillin Ampicillin/ sulbactam Amoxicillin/ clavulanate

Penicillin G Penicillin VK

Extended-spectrum Piperacillin Mezlocillin Ticarcillin Carbenicillin Ticarcillin/ clavulanate Piperacillin/ tazobactam

Treatment with Penicillins and Cephalosporins

TABLE 2

Classiﬁcation of Cephalosporins

First generation Cefadroxil Cephalexin Cefazolin Cephradine

125

Second generation

Third generation

Fourth generation

Cefaclor Cefprozil Cefuroxime Cefamandole Cefoxitin Cefotetan Loracarbef

Cefdinir Cefixime Ceftibuten Cefpodoxime Cefotaxime Ceftizoxime Ceftriaxone Cefoperazone Ceftazidime Cefditoren

Cefepime

producing and penicillinase non-producing Staphylococcus aureus, as well as Streptococcus sp. Second-generation cephalosporins are active against the organisms susceptible to ﬁrst-generation agents plus activity against Haemophilus inﬂuenzae, including ampicillin-resistant strains. The agents cefoxitin and cefotetan also exhibit some useful anaerobic activity. The third-generation cephalosporins are less active against gram-positive organisms but exhibit enhanced gram-negative activity, particularly for Enterobacteriacae. Activity against Streptococcus pneumoniae is quite adequate, and ceftriaxone is commonly used for community-acquired respiratory tract infection. Other third-generation agents, ceftazidime and cefoperazone, have activity against Pseudomonas aeruginosa. The fourth-generation cephalosporin, cefepime, has expanded gram-negative coverage compared with the third-generation agents against organisms producing inducible h-lactamases, and also is active against Pseudomonas aeruginosa. This drug is generally not used in treatment of community-acquired respiratory tract infection; however, it does have good activity against S. pneumoniae and could be used empirically in the setting of severe CAP when gram-negative rods are also a possibility as the infecting organism. The oral cephalosporins with the best antimicrobial activity against Streptococcus pneumoniae with MIC50s of V0.1 mg/L are cefuroxime axetil, cefditoren, and cefpodoxime . Cefaclor, cephalexin, ceﬁxime, and loracarbef have MIC50s of V0.2–1 mg/L, and the least active drugs are ceftibuten and cefadroxil, with MICs of > 1 mg/L [7]. Activity against H. inﬂuenzae varies depending on whether or not the organism produces h-lactamase. The best activity against non–h-lactamase producing strains is seen with ceﬁxime, ceftibuten, cefditoren, and cefpodoxime. Loracarbef and cephalexin are inactive against H. inﬂuenzae. As with the penicillins, the activity of the

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cephalosporins against the atypical pathogens is poor. The antimicrobial activity of antimicrobials from clinical isolates and in vitro data versus the common respiratory pathogens are shown in Tables 3 and 4. The ranking of these drugs solely on the basis of the MIC values can be misleading. Other factors, such as pharmacokinetic proﬁle and protein

TABLE 3

Antimicrobial Activity for Common Respiratory Pathogens from Clinical Isolates from Surveillance Studies in North America Drug

Streptococcus pneumoniae Penicillin G Amoxicillin Amoxicillin/clavulanate Cefpodoxime Cefuroxime axetil Cefaclor Cefixime Ceftibuten Cefprozil Ceftriaxone Haemophilus influenzae Penicillin G Amoxicillin Amoxicillin/clavulanate Cefuroxime axetil Cefaclor Cefprozil Cefixime Cefpodoxime Ceftibuten Ceftriaxone Moraxella catarrhalis Penicillin G Ampicillin Amoxicillin/clavulanate Cefuroxime axetil Cefaclor Cefprozil Cefixime Cefpodoxime Ceftriaxone Source: Refs. 54 through 57.

MIC50

MIC90

0.03 0.06 0.25 0.03 0.06 0.5 0.5 0.03 2 0.015

1–2 1–2 1–2 1–4 4 >64 >64 0.12 8 0.03–1

0.5 0.5 0.5 1 4 2–4 V0.03 0.06 V0.03 0.015

>16 >8 1–2 2 16 8–16 0.06 0.12 0.12 0.03

>4 2 V0.25 1 1 2 0.25 0.5 0.5

16 8 0.25 2 2 8 0.5 1 1

Treatment with Penicillins and Cephalosporins

TABLE 4

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In Vitro Antimicrobial Activity

Drug Streptococcus pneumoniae Cefuroxime Cefpodoxime Cefixime Haemophilus influenzaeb Amoxicillin/clavulanate Cefuroxime Cefixime Cefpodoxime Cefditoren Ceftibuten Loracarbef Cefaclor Moraxella catarrhalisc Amoxicillin/clavulanate Cefaclor Cefuroxime Cefixime Cefpodoxime Ceftibuten Cefditoren Loracarbef

MIC50

MIC90

0.01 0.03 0.5

4 4 32

0.5 1 0.12 0.06 0.008 0.06 2 4

2 4 1 0.125 0.015 0.06 8 32

0.06 0.5 0.5 0.06 0.06 0.12 0.03 V0.25

1 4 2 0.5 0.5 4 1 2

a

Includes h-lactamase positive and negative organisms. a Source: Refs. 58 and 59 b Source: Refs. 60 through 63. c Source: Refs. 64 through 67.

binding, will make a large diﬀerence in the relative activity of these drugs. Indeed, only free drug is microbiologically active, and the relative activity of the penicillins and cephalosporins should be graded on the fraction of the dosing interval that free drug spends above the MIC values for the target pathogens. There are diﬀerences among the h-lactams with regard to the fraction of the dosing interval necessary for coverage to achieve a speciﬁc desired endpoint (e.g., stasis or maximal cell kill). Given that true betweenpatient variability in pharmacokinetics exists for all drugs, the most robust way to gauge the activity of these agents for the target pathogens is to perform large Monte Carlo simulations in which the evaluative criterion is the fraction of subjects in the simulation that achieve the target free drug time above MIC.

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TABLE 5

Preston and Drusano S. pneumoniae NCCLS Interpretive MIC Breakpoints (Ag/mL)

Drug Penicillin Amoxicillin Amoxicillin F clavulanate Cefixime Cefpodoxime Cefaclor Cefuroxime axetil Loracarbef Ceftriaxone and cefotaxime non-meningeal isolates meningeal isolates

Susceptible V0.06 V2.0 V2.0 V0.5 <1.0 <1.0 2.0 1.0 0.5

Intermediate 0.12–1 4.0 4.0 No breakpoints set 1.0 2.0 2.0 4.0 2.0 1.0

Resistant z2.0 z8.0 z8.0 z2.0 z4.0 z4.0 z8.0 4.0 2.0

Penicillin-Resistant Streptococcus pneumoniae The current interpretive MIC breakpoints for penicillin as determined by the National Committee for Clinical Laboratory Standards (NCCLS) are V0.06 Ag/mL (susceptible), 0.12–1.0 Ag/mL (intermediate), and z2.0 Ag/mL (resistant) [8]. Additional susceptibility breakpoints are shown in Table 5. In the United States, the prevalence of penicillin-non-susceptibility has risen from 4% in the 1980s to approximately 35% in 1997–1998 [9]. The prevalence of Streptococcus pneumoniae resistance to the cephalosporins is also high for cefaclor (34–78%, [10–13] and cefuroxime axetil (16– 37%) [10,12–14]. Cefotaxime and ceftriaxone are more active with resistance rates of 4–11% [10,13,15]. The presence of a h-lactamase inhibitor oﬀers no advantage in penicillin-resistant Streptococcus pneumoniae because the mechanism of resistance is not h-lactamase, but an altered PBP. PHARMACOKINETICS AND PHARMACODYNAMICS The pharmacokinetics of h-lactams vary among compounds. Amoxicillin is well absorbed with or without clavulanate. A twice-daily extended-release formulation of amoxicillin/clavulanate (Augmentin XR) has received FDA approval. The drug should be given in a dosage of 2000/125 mg twice daily (two tablets twice daily) and has the advantage of providing enhanced amoxicillin drug exposure versus resistant Streptococcus pneumoniae. The oral cephalosporins are commonly used in the outpatient setting for treatment of respiratory tract infection. The pharmacokinetics of the oral h-lactams commonly used for this indication is summarized in Table 6.

Treatment with Penicillins and Cephalosporins

TABLE 6

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Pharmacokinetics of Cephalosporins

Drug

Dose, mg

Cmax, mg/L

T 1⁄2, hr

Protein binding, %

Ref.

Ceftibuten Cefpodoxime Cefixime Cefprozil Cefaclor Cefuroxime axetil Cefdinir Loracarbef Cefditoren Ceftriaxone Cefotaxime

200 200 400 500 375 250 600 400 400 1000 1000

10.8–12.4 2.5 3.7–4.6 10 5.4 4.1 2.87 14–15.4 4.4–4.6 95 102

2.5–3.2 2–3 3–4 1–2 0.5–1 1–2 1.7–1.8 1.2 1.3–2 5.8–8.7 0.8–1.4

63 18–33 50–65 35–45 25 33–50 60–70 25 88 83–96 27–38

68 69, 70 71, 72 73, 74 75 76 77 78, 79 80, 81 82, 83 84, 85

The h-lactams exhibit relatively concentration-independent bactericidal activity, meaning that at concentrations greater than 2–4 times the MIC, no additional killing activity is seen [16]. In addition, regrowth of most organisms will occur soon after serum drug levels fall to below the level of the MIC [17], indicating that a persistent eﬀect (PAE, PASME, etc.) is short or absent. Optimization of duration of exposure, or time that non–protein-bound serum concentrations remain above the MIC, would be the most appropriate way to maximize the likelihood of bacterial eradication and subsequently a positive outcome. There has been a signiﬁcant amount of animal model research that has examined this issue. The duration of time needed above the MIC was examined in a neutropenic mouse model infected with Klebsiella pneumoniae pneumonia. A bacteriostatic and bactericidal eﬀect was seen when the time above MIC was 30–40% and 60–70%, respectively [18]. The penicillins demonstrated a slightly lower percentage of time needed above the MIC, possibly attributable to diﬀerences in rates of killing [19]. An alternative hypothesis would be that the diﬀerences among h-lactam classes (penicillins, cephalosporins, carbapenems) in the fraction of the dosing interval for which free drug concentrations need to exceed the MIC to achieve a speciﬁc endpoint (stasis, maximal cell kill, etc.) may be related to the binding to diﬀerent PBPs and the manner in which they bind to the PBPs. Streptococcus pneumoniae infection (strains that were penicillin susceptible, intermediate, and resistant) was examined in an animal model utilizing

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penicillins or cephalosporins. A relationship between mortality and time above MIC was developed. If the time above the MIC was 20% or less, mortality after 4 days of therapy was 80–100%. At a time above the MIC of 40–50%, the mortality was 0–20%, and at a time above the MIC of greater than 50%, the mortality was 0% [20]. A relationship between time above the MIC and bacteriological cure for patients with acute otitis media infected with S. pneumoniae and H. inﬂuenzae was developed from clinical trial data from several studies [20,21]. Time above MIC of greater than 40% was needed to achieve an 85–100% bacterial eradication rate. There did not appear to be diﬀerences in time above MIC needed between organisms. Using a time above MIC goal of greater than 40%, common dosage regimens of several h-lactams were examined in a pediatric population to determine if suﬃcient drug concentrations would meet that target versus penicillin-intermediate or-resistant Streptococcus pneumoniae [20,21]. Amoxicillin and cefaclor were dosed 13.3 mg/kg TID and cefuroxime axetil was dosed 15 mg/kg BID. For penicillin-intermediate strains, two oral agents, cefuroxime axetil and amoxicillin, provided time above MICs for greater than 40% of the dosing interval but cefaclor did not, with a time above MIC of 0– 20%. For resistant strains, only amoxicillin provided suﬃcient drug exposure. All parenteral h-lactams, including ampicillin, penicillin G, cefotaxime, and ceftriaxone, met the target for both intermediate and resistant organisms. In a clinical trial setting, the parenteral h-lactams performed well, even versus penicillin-resistant strains [22]. The ability of h-lactams to meet a target of serum concentrations exceeding the MIC for 40% of the dosing interval was examined using 4,489 clinical isolates of Streptococcus pneumoniae from a large surveillance study. For penicillin-susceptible pneumococcus, serum concentrations achieved for cefprozil, cefaclor, ceﬁxime, cefpodoxime, and cefuroxime axetil were suﬃcient to meet the target. However, for penicillin-intermediate strains, only cefprozil, cefpodoxime, and cefuroxime axetil met the target. None of the drugs examined achieved suﬃcient concentrations for penicillin-resistant isolates [23]. The treatment guidelines for acute bacterial rhinosinusitis explicitly addressed the pharmacodynamic issue of the fraction of the time standard doses of h-lactams exceeded the MIC for 40–50% of the dosing interval for a large collection of isolates [24]. As previously demonstrated [23], many of the cephalosporins were poor in their ability to attain the target. These results are presented for the h-lactams in Table 7. Of the oral cephalosporins listed, only cefpodoxime, cefprozil, and cefuroxime attain the target at the PK/PD breakpoint for a reasonable percentage of the time (only 50–60%) for penicillin-intermediate pneumococci (n = 284). For fully penicillin-resistant

Source: Ref. 24.

100 100 100 47.3 95.3 100 99.2 99.8 15.8

0.5 1 0.5 1 1 0.5

Penicillin = susceptible S. pneumoniae (%) (n = 973)

4 2 4

PK/PD Susceptibility Breakpoint (Ag/mL)

7.4 28.5 48.2 57.7 59.9 3.5

100 100 100

Penicillin = intermediate S. pneumoniae (%) (n = 284)

0.2 0.4 0 0.4 0 0

79.7 65.6 80.1

Penicillin = resistant S. pneumoniae (%) (n = 503)

Percentage of Respiratory Tract Isolates Susceptible at PK/PD Breakpoints

High-dose amoxicillin Amoxicillin/clavulanate High-dose amoxicillin/ clavulanate Cefaclor Cefixime Cefpodoxime Cefprozil Cefuroxime Loracarbef

Drug

TABLE 7

2.3 99.9 99.9 18.2 79.6 9.7

61.1 97.0 99.6

H. influenzae (%) (n = 1919)

5.4 100 64.1 6.4 37.3 4.9

13.7 100 100

M. catarrhalis (%) (n = 204)

Treatment with Penicillins and Cephalosporins 131

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pneumococci (n = 505), none of the cephalosporins attain the target, even at the 1% level. High-dose amoxicillin and amoxicillin/clavulanate, on the other hand, attain the target up to 80% of the time, even for fully penicillin-resistant isolates. For Hemophilus inﬂuenzae (n = 1919), only ceﬁxime, cefuroxime, and cefpodoxime attain the target 80% of the time or more among the listed cephalosporins. It should be noted that some agents were not included in this list (ceftibutin, cefdinir, and cefditoren). Amoxicillin plus clavulanate, on the other hand, attains the target for more than 95% of the time for this pathogen. It is clear that many oral cephalosporins are poorly active for the most important target pathogens seen in community-acquired upper and lower respiratory tract infections. If used in this setting, the agent employed should be chosen carefully, as there are major diﬀerences among these agents. Factors to consider include the severity of the illness, the possible adverse events attached to a failure of therapy, and the geographical locale, including the likelihood of encountering a strain of Streptococcus pneumoniae that is intermediate in its penicillin sensitivity or is fully penicillin resistant. It should also be noted that this analysis likely overestimates the activity of all the h-lactams, as total drug concentrations were employed in the analysis. Only free drug is microbiologically active [25]. Ceftibuten, ceﬁxime, cefdinir and cefditoren all have protein binding exceeding 50% (Table 6), indicating that correcting for free drug will, in essence, decrease the pharmacodynamic MIC breakpoint by one further dilution. Finally, overuse of these agents (poorly active cephalosporins) may have an adverse ecological impact, in terms of amplifying the number of strains of Streptococcus pneumoniae that are penicillin-resistant. It has been demonstrated that utilization patterns of both macrolides and h-lactams aﬀected the number of resistant isolates of pneumococcus found in their diﬀerent areas of surveillance [26]. In this analysis, while aminopenicillin use adversely aﬀected the number of resistant isolates, cephalosporins had a stronger association with this outcome. Again, this ﬁnding provides more importance to the idea that the overuse of all antibiotics should be avoided and that when necessary, drugs that are likely to attain the target of optimal antibacterial eﬀect should be employed. ADVERSE EFFECTS Oral penicillin and cephalosporins are generally well tolerated, with the most common side eﬀects being gastrointestinal intolerance, including nausea, vomiting, and diarrhea. The incidence of diarrhea with amoxicillin/clavulanate is approximately 12–15%. Clostridium diﬃcile colitis has been reported to occur with both penicillin and cephalosporin use.

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A maculopapular rash can occur in 5–10% of patients receiving amoxicillin and is generally self-limited. h-Lactam use may also be associated with an increase in liver transaminases. Other toxicities associated with cephalosporins that may occur include eosinophilia, thrombocytopenia, leukopenia, and a positive Coombs test. Cefpodoxime administration is associated with a metallic taste. Penicillin hypersensitivity can occur in 1–10% of patients [27], and can range from a rash to anaphylaxis. Though potentially fatal, the incidence of anaphylaxis is low at about 0.004–0.015% of patients [28]. Sensitivity can result secondary to antibodies to the breakdown products of penicillin, including the major determinant (benzylpenicilloyl) and the minor determinants. These determinants can serve as an antigen to elicit an immune response [29]. The most immediate reaction is a type I or anaphylactic reaction involving IgE antibodies, which cause degranulation of mast cells and subsequent physiological reactions leading to urticaria, bronchoconstriction, and laryngeal edema [30]. Other types of hypersensitivity reactions to penicillins may occur, including a type II cytotoxic reaction resulting in a hemolytic anemia, a type III reaction resulting from antigen-antibody complexes depositing in major organs and leading to a serum sickness–like syndrome, and a type IV delayed hypersensitivity reaction of contact dermatitis or acute interstitial nephritis. Types II and III reactions usually occur after prolonged periods of penicillin use on the order of several weeks [31]. Allergic reactions may occur with cephalosporin use in a similar fashion to penicillins. The rate of cross-reactivity in patients with a penicillin allergy varies, but is usually reported to be 2–10% [32] but may be lower [33]. This may be due to the fact that the cephalosporanic acid nucleus is unstable once the h-lactam bond is lysed, resulting in the absence of minor degradation products for these agents. In patients with a history of an anaphylactic reaction to penicillin, cephalosporin use should be avoided. Cefaclor has been associated with a serum sickness–like reaction with an incidence of 0.5%. Manifestations include a maculopapular rash or erythema multiforme, pruritis, and arthritis, arthralgia, irritability, and fever [34,35]. This syndrome is most common in patients under the age of 6 years, and management consists of drug discontinuation, antihistamines, and corticosteroids for symptomatic relief. CLINICAL UTILITY IN TREATMENT OF COMMUNITY-ACQUIRED RESPIRATORY TRACT INFECTION The choices for treatment of community-acquired respiratory tract infection can include several diﬀerent antimicrobial classes, including macrolides,

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ﬂuoroquinolones, and h-lactams. This section will focus on the utility of hlactams for this indication. Because Hemophilus inﬂuenzae is a common pathogen in community-acquired respiratory tract infections and often carries a h-lactamase, amoxicillin and penicillin VK are not commonly used for treatment of community-acquired respiratory tract infection. Instead, other h-lactam choices include amoxicillin/clavulanate and the second- and third-generation cephalosporins, cefuroxime axetil, cefpodoxime, cefaclor, loracarbef, ceﬁxime, and ceftibuten. Common dosages for these and other agents are listed in Table 8. Pharyngitis/Tonsillitis The oral cephalosporins are eﬀective in treating this infection; however there are no data on the eﬃcacy of these agents in subsequent prevention of rheumatic fever. Penicillin V or benzathine penicillin G are still considered the drugs of choice for treatment of group A Streptococcus infection because of their prevention of primary rheumatic fever and cost considerations [36]. In patients allergic to penicillin, erythromycin is an alternative agent. A ﬁrstgeneration cephalosporin, such as cephalexin or cefadroxil, may be considered in patients without a history of anaphylaxis to penicillin. Penicillin VK is dosed at 250 mg b.i.d. or t.i.d. in children. Adolescents and adults receive a dose of either 250 mg t.i.d. or q.i.d., or 500 mg b.i.d. Once-

TABLE 8 Adult Dosage of h-lactams in Treatment of Community Acquired Respiratory Tract Infections Generic name (Brand) Cefpodoxime (Vantin) Pharyngitis and tonsillitis Cefprozil (Cefzil) Cefixime (Suprax) Cefdinir (Omnicef) Cefaclor (Ceclor) Acute exacerbation of chronic bronchitis Pharyngitis/tonsillitis Ceftibuten (Cedax) Cefuroxime axetil (Ceftin) Loracarbef (Lorabid) Cefditoren (Spectracef) Ceftriaxone (Rocephin)

Common dosage 200 mg PO q.12hr 10–14 days 100 mg PO q.12hr 5–10 days 250–500 mg PO q.12hr 10 days 400 mg PO q.24hr or 200 mg PO q.12hr for 10–14 days 600 mg PO q.d. or 300 mg PO q.12hr for 10–14 days 500 mg PO q.12hr 7d 375 mg PO q.12hr 10 days 400 mg PO q.d. 10 days 250–500 mg q.12hr 7–10 days 200–400 mg PO q.12hr 7–10 days 400 mg PO b.i.d. 10 days 1–2 g I.M./I.V. q.24hr 10–14 days

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daily penicillin VK is not eﬀective [37]. Several agents are FDA approved for once-a-day administration for streptococcal pharyngitis, including the oral cephalosporins cefadroxil, ceﬁxime, and cefdinir and a macrolide, azithromycin. The duration of therapy for penicillin VK is 10 days to achieve maximal rates of pharyngeal pathogen eradication. While shorter-course therapy of 5 days or less has demonstrated eﬃcacy and has been approved by the FDA for cefdinir, cefpodoxime, and azithromycin, it is not recommended at this time because of concerns over study design and the broad spectrum of the agents and increased cost over penicillin VK [38]. Acute Exacerbation of Chronic Bronchitis Acute exacerbation of chronic bronchitis (AECB) is a condition associated with chronic obstructive pulmonary disease (COPD) and is most commonly caused by H. inﬂuenzae, S. pneumoniae, and M. catarrhalis. Treatment with antibiotics has been shown to lengthen the exacerbation-free period [39]. Treatment is often empiric as it is not always possible to get an appropriate sample for microbiological testing due to the outpatient nature of cases of this infection. Coverage of the most common organisms causing this infection is therefore necessary. First-line agents such as amoxicillin, doxycycline, and trimethoprim/ sulfamethoxazole were used extensively in the past to treat these infections, but increasing prevalence of resistance [40], such as h-lactamase production aﬀecting the activity of h-lactams, has limited the use of these agents, particularly in patients with comorbidities. A h-lactam/h-lactamase inhibitor combination or a cephalosporin such as cefuroxime are some alternative second-line agents that can be used to treat this infection, particularly in more complicated cases and in patients with more symptoms where h-lactam resistance is possible [41,42]. In general, these agents are more expensive that amoxicillin, but some data have suggested that they may be more costeﬀective [43]. Acute Maxillary Sinusitis Acute sinusitis is a common infection, with about 20 million cases per year in the United States [44]. Despite the fact that symptoms of acute sinusitis can improve without antibiotic therapy, antibiotics have been shown to increase the speed of symptom resolution [45] and decrease the incidence of clinical failures by as much as 50% [46]. Also, antibiotic therapy may be cost-eﬀective [46]. It is important to note, however, that acute sinusitis is similar to acute otitis media in that high clinical success rates seen in clinical trials of antibiotics may not translate to bacteriological eﬃcacy. This phenomenon

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is termed the ‘‘Pollyanna phenomenon,’’ meaning that symptoms may resolve despite inadequate antimicrobial therapy and that these drugs may appear more eﬀective clinically than they really are as measured by antimicrobial activity [47]. This may explain why clinical success may be discordant with predicated success based on pharmacodynamics. The causative pathogens include H. inﬂuenzae, S. pneumoniae, and less frequently, M. catarrhalis. The h-lactams are commonly used to treat this infection. First-line therapy includes the inexpensive agents amoxicillin and trimethoprim/sulfamethoxazole. If there is suspicion of penicillin-resistant pneumococcus, the dose of amoxicillin should be increased to a maximum of 3 g/day to attempt to overcome this resistance. Use of second-line agents such as the second- and third- generation cephalosporins (cefprozil, cefuroxime axetil, cefpodoxime) and amoxicillin/ clavulanate should be considered as a ﬁrst choice in therapy in patients who have received prior antibiotic therapy in the past 4–6 weeks [44], if ﬁrst-line therapy failed, if the patient is younger than 2 years, if there is a smoker in the family or a child in a day-care facility, or if resistance is common in the community [48]. The utility of cefaclor and loracarbef is limited due to decreasing activity versus resistant H. inﬂuenzae and only fair activity against Streptococcus pneumoniae, particularly resistant organisms. Community-Acquired Pneumonia The organisms that most commonly cause community-acquired pneumonia (CAP) include Streptococcus pneumoniae, H. inﬂuenzae, M. catarrhalis, and the atypicals, Mycoplasma pneumoniae, Chlamydia pneumoniae, and Legionella pneumophila. The h-lactams are inactive against the atypical pathogens; therefore, empiric regimens that include a h-lactam must also be combined with a macrolide or doxycycline to provide adequate coverage for these potential pathogens. The role of h-lactams for empiric therapy for CAP in the era of resistant Streptococcus pneumoniae has been supported in various levels by the Centers for Disease Control and Prevention (CDC) guidelines [49], as well as guidelines from the American Thoracic Society (ATS) [50] and Infectious Diseases Society of America (IDSA) [51]. The CDC guidelines for empiric CAP therapy include a recommendation for certain h-lactams for initial empiric therapy if the penicillin MIC is 2 mg/L or lower. The agents recommended for oral therapy include cefuroxime, cefpodoxime, high-dose amoxicillin (1g PO q8h), or amoxicillin/clavulanate 875 mg twice daily. For intravenous therapy, cefotaxime, ceftriaxone, or ampicillin/sulbactam can be used. These guidelines also illustrate the potential role of the antipneumococcal ﬂuoroquinolones, particularly if the penicillin MIC is 4 mg/L or higher.

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In developing their guidelines for empiric therapy for CAP, the ATS stratiﬁed outpatients according to presence or absence of cardiopulmonary disease or other modifying factors, such as age older than 65, immunosuppressive illness, or other comorbidities. They did not recommend a h-lactam for outpatients with no modifying factors or a history of cardiopulmonary disease. If the patient does have cardiopulmonary disease or other modifying factors, a h-lactam such as oral cefpodoxime, cefuroxime, high-dose amoxicillin, amoxicillin/clavulanate, or parenteral ceftriaxone followed by oral cefpodoxime is recommended in conjunction with a macrolide (or doxycycline) as a treatment alternative. According to the ATS guidelines, for inpatients who are not in the intensive care unit with cardiopulmonary disease and/or modifying factors, an intravenous h-lactam such as cefotaxime, ceftriaxone, ampicillin/ sulbactam, or high-dose ampicillin plus a macrolide (or doxycycline) is recommended. In hospitalized patients without cardiopulmonary disease or modifying factors, a h-lactam is recommended only in case of a macrolide allergy/intolerance. In ICU-admitted patients, an intravenous h-lactam such as ceftriaxone may be given with an intravenous macrolide. If patients are at risk for Pseudomonas aeruginosa infection, choices include cefepime, imipenem, meropenem, or piperacillin/tazobactam. If resistant Streptococcus pneumoniae is suspected, certain h-lactams should not be used secondary to possible decreased eﬃcacy. These agents include ﬁrst-generation cephalosporins, cefaclor, and loracarbef [50]. The IDSA guidelines do not recommend a h-lactam for empiric CAP therapy for outpatients. If the patient needs hospitalization, either in a general medical ward or the ICU, a h-lactam (cefotaxime, ceftriaxone, or a h-lactam/ h-lactamase inhibitor) plus a macrolide is one of two preferred choices (the other being a ﬂuoroquinolone with anti-pneumococcal activity) [51]. For treatment of pneumonia due to penicillin-susceptible Streptococcus pneumoniae (MIC V 1.0 Ag/mL, amoxicillin, the oral cephalosporins (such as cefpodoxime, cefprozil, or cefuroxime), or parenteral agents such as ceftriaxone are eﬀective [51,52]. In settings with a Streptococcus pneumoniae MIC of 2 Ag/mL or greater, treatment can be guided on the basis of susceptibility testing; appropriate agents may include high-dose ampicillin, cefotaxime, ceftriaxone, and Augmentin XR. H. inﬂuenzae and M. catarrhalis pneumonia may be treated with the hlactams in the form of a second- or third-generation cephalosporin or a hlactam/h-lactamase inhibitor. h-Lactam/h-lactamase inhibitor combinations are also useful for treatment of an anaerobic pneumonia [51]. Treatment outcomes associated with initial h-lactam–containing regimens for empiric treatment of pneumonia were examined in a 12,945 patient retrospective review of elderly Medicare inpatients [53]. Approximately three

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quarters of the population were community-dwelling, with the remainder admitted to a long-term-care facility. Of the regimens used initially, the ones associated independently with a decreased 30-day mortality included (1) a second-generation cephalosporin plus a macrolide, (2) a non-pseudomonal third-generation cephalosporin plus a macrolide, and (3) a ﬂuoroquinolone. The regimens associated with an increase in 30-day mortality include a hlactam/h-lactamase inhibitor plus a macrolide and an aminoglycoside plus another agent. In the 75% of patients who were community-dwelling, only initial therapy with a non-pseudomonal third-generation cephalosporin plus a macrolide was associated with decreased mortality; however, this may have been due to a smaller sample size. It is unclear why the h-lactam/h-lactamase inhibitor plus a macrolide regimen did not perform well. Possible reasons include suboptimal activity against penicillin-resistant Streptococcus pneumoniae, use of this regimen in patients suspected of having aspiration pneumonia, infection with an unrecognized pathogen for which the regimen was not eﬀective, or that it was a chance ﬁnding because the study was a retrospective analysis. SUMMARY The penicillins and cephalosporins are commonly used for treatment of community-acquired respiratory tract infections and continue to have a role in the era of drug-resistant Streptococcus pneumoniae. They remain popular because of their well-deﬁned safety proﬁle and their activity against common respiratory pathogens. The eﬃcacy of a speciﬁc h-lactam against speciﬁc respiratory pathogens (including drug-resistant Streptococcus pneumoniae) varies based on intrinsic antimicrobial activity against the infecting organism and the pharmacokinetics and pharmacodynamics of the drug. REFERENCES 1. Price KE, Gourevitch A, Cheney LC. Biological properties of semisynthetic penicillins: structure-activity relationships. Antimicrob Agents Chemother 1966; 13:670–708. 2. Marshall WF, Blair JE. The cephalosporins. Mayo Clin Proc 1999; 74:187–195. 3. Tomasz A. The mechanism of the irreversible antimicrobial eﬀects of penicillin: how the beta-lactam antibiotics kill and lyse bacteria. Annu Rev Microbiol 1979; 33:113–117. 4. Yocum RR, Waxman DW, Strominger JL. The mechanism of action of penicillin. J Biol Chem 1980; 255:3977–3986. 5. Markiewicz Z, Tomasz A. Variation in penicillin-binding protein patterns of penicillin-resistant clinical isolates of pneumococci. J Clin Microbiol 1989; 27: 405–410. 6. Hakenbeck R, Grebe T, Zahner D, Stock JB. h-lactam resistance in Strep-

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8 Treatment of Community-Acquired Respiratory Tract Infections with Other Antibiotics William A. Craig and David R. Andes University of Wisconsin Madison, Wisconsin, U.S.A.

Besides the h-lactams, macrolides, and ﬂuoroquinolones, a variety of drugs have been used to treat community-acquired pulmonary infections: the tetracyclines (primarily doxycycline), clindamycin, trimethoprim-sulfamethoxazole, vancomycin, and linezolid. The appearance of strains of Streptococcus pneumoniae resistant to some of these drugs has limited their current use in upper respiratory tract infections, acute exacerbations of chronic bronchitis, and community-acquired pneumonia [1]. Others such as vancomycin have been used primarily in hospitalized patients with severe pneumococcal pneumonia. The optimal dosing of these drugs for respiratory infections is dependent on the drug’s pharmacokinetics and pharmacodynamics (PK/PD) against the infecting pathogens. For upper respiratory tract infections such as sinusitis and otitis media, concentrations in serum are often predictive of eﬃcacy [2]. However, for pulmonary infections, there is increasing evidence that the concentrations in lung secretions, such as epithelial lining ﬂuid (ELF), are very important for determining the outcome 145

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of treatment. This chapter will review the current available data on the activity of these drugs against respiratory pathogens and their distribution in respiratory tissues. TETRACYCLINES The tetracyclines have been used for respiratory tract infections for many years. Doxycycline is the primary tetracycline derivative used for communityacquired pneumonia. It is recommended by the American and Canadian Thoracic Societies, the Infectious Diseases Society of America (IDSA), and the Canadian Infectious Disease Society as an alternative to macrolides for mild to moderate disease in patients treated as outpatients [3–5]. It has also been shown to be eﬀective in hospitalized patients with community-acquired pneumonia [6]. However, the increasing appearance of tetracycline-resistant S. pneumoniae has called into question the empiric use of doxycyline in community-acquired pneumonia. The incidence of tetracycline resistance in North America with pneumococci has varied between 12% and 17% in the large surveillance studies [7–9]. However, higher rates of resistance have been reported in Asia, Europe, Latin America, and some locations in the United States [8–10]. However, doxycycline is more potent than tetracycline, and lower resistance rates have been observed when doxycycline susceptibility is determined. For example, Shea and Cunha [11] observed 20% resistance to tetracycline but only 5% resistance to doxycycline in a survey of drug susceptibility for 256 strains of S. pneumoniae. Doxycyline has maintained good activity against Haemophilus inﬂuenzae and Moraxella catarrhalis. MICs are usually less than 2 Ag/mL for both organisms. The drug also has excellent activity against the common atypical pathogens. The pharmacodynamics of doxycycline against strains of S. pneumoniae with varying MICs has recently been evaluated in the neutropenic murine thigh-infection model [12,13]. The drug does not exhibit concentration-dependent killing, but it does produce prolonged postantibiotic eﬀects (PAEs). The 24-hr AUC/MIC ratio is the important PK/PD parameter determining eﬃcacy of doxycyline [12]. More limited studies have demonstrated similar ﬁndings with minocycline [14]. The magnitude of the 24-hr AUC/MIC required for a bacteriostatic eﬀect varies from 12 to 55 with a mean of 25 when free drug is used for calculation of the AUC [13]. This magnitude or target is very similar to the 24-hr AUC/MIC of free drug required for eﬃcacy of various macrolides [15]. The presence of neutrophils in the mouse model enhances the activity of doxycycline approximately two- to three-fold [16]. If one translates the data from the mouse model to the pharmacokinetics of doxycyline in humans, dosing regimens of 100 mg twice daily would provide therapeutic free drug concentrations in plasma for organisms with MICs up

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to 2 Ag/mL. However, there are few if any clinical data with tetracyclineresistant strains of S. pneumoniae to determine if organisms with MICs above 2 Ag/mL have a high failure rate in patients with community-acquired pneumonia. The concentrations of doxycycline in respiratory secretions are generally reported to be lower than in either serum or plasma. For example, sputum, middle ear ﬂuid, and sinus ﬂuid concentrations of doxycycline are usually 17–57% of serum values [17–19]. Although ELF levels of doxycyline have not been reported, bronchial secretions of minocycline are 3 to 5 times higher than in serum [18]. One would expect the concentrations of doxycycline in bronchial secretions to be of similar magnitude. High concentrations in respiratory secretions might increase the eﬃcacy of empiric doxycycline therapy even when some resistant strains are present. High penetration of macrolides into respiratory secretions has been used as an explanation for the small number of clinical failures despite high levels of resistance in microbiology surveys [20]. Moderately large clinical trials with doxycycline have shown equivalent eﬃcacy to macrolides and ﬂuoroquinolones [21–23]. However, the drug’s eﬃcacy against tetracycline-resistant strains in not known. CLINDAMYCIN Clindamycin has been used more for the therapy of aspiration pneumonia and lung abscesses than for treatment of community-acquired pneumonia. It has also occasionally been used for pneumococcal otitis media. Clindamycin is active against many pneumococci, but its activity against H. inﬂuenzae, M. catarrhalis, and atypical pathogens is less than that of the tetracyclines and macrolides [9]. In Europe, most macrolide-resistant pneumococci are also resistant to clindamycin [8,9]. This is because macrolide resistance in Europe is due primarily to the presence of Erm genes and the methylation of the 23s ribosome. In North America, 70–80% of macrolide-resistant S. pneumoniae are susceptible to clindamycin. Drug eﬄux due to the presence of Mef genes is the primary mechanism of macrolide resistance in North America, and clindamycin is not a substrate for the eﬄux pump. The penetration of clindamycin into bronchial secretions is only about 60% of drug concentrations in serum [17,19]. The amount or AUC of clindamycin distributing into pleural ﬂuid is also similar to values observed in serum [19,24]. However, the peak levels in pleural ﬂuid are lower than in serum, whereas the trough levels are higher in pleural ﬂuid than in serum. One would also expect the concentrations of clindamycin in middle ear ﬂuid to be similar to that in serum. Initial studies on the pharmacodynamics of clindamycin in the neutropenic murine thigh-infection model suggested that the important PK/PD parameter was time above MIC [25]. On the other hand,

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recent studies with multiple isolates of S. pneumoniae suggest that the 24-hr AUC/MIC is the major determinant of in vivo eﬃcacy [26]. The magnitude of the 24-hr AUC/MIC using free drug required for a bacteriostatic eﬀect ranged from 16 to 30. The presence of neutrophils reduced the target requirement at least four-fold [16]. Based on human drug concentrations and protein binding of 78%, a dose of 300 mg 3 times a day would provide a 24-hr AUC/MIC that would exceed the target value generated in animal models for organisms with MICs of 0.5 Ag/mL or less. Thus, this dose should be very eﬀective for susceptible S. pneumoniae for which the MICs are usually 0.25 Ag/mL or less [9]. Trials of clindamycin in pneumococcal pneumonia have validated the high eﬃcacy of the drug for this infection [27]. TRIMETHOPRIM-SULFAMETHOXAZOLE Trimethoprim-sulfamethoxazole has been one of the major drugs for treatment of exacerbations of chronic bronchitis. In the pediatric age group, it has also been a commonly used drug for treatment of otitis media and community-acquired pneumonia. However, resistance rates to trimethoprim-sulfamethoxazole of S. pneumoniae have been signiﬁcantly increasing over the past decade. In the large surveillance studies, trimethoprim-sulfamethoxazole resistance in North America for S. pneumoniae has ranged from 20% to 38% [8,9]. Resistance has been higher in Asia and Latin America [8]. Trimethoprim-sulfamethoxazole resistance has also been observed for H. inﬂuenzae at a frequency of 14–18% in most areas, but 31% in Latin America [9]. Trimethoprim penetrates better into respiratory secretions than sulfamethoxazole. Concentrations in sputum, middle ear ﬂuid, and sinus ﬂuid are about 119–173% of serum for trimethoprim and only 20–27% of serum for sulfamethoxazole [18,19]. Trimethoprim concentrations in bronchial secretions are 4 to 10 times those in serum [28]. Sulfamethoxazole exhibits concentrations in bronchial secretions that are 60–100% of those in serum. Very little is known about the pharmacodynamics of trimethoprim-sulfamethoxazole. The drug exhibits concentration-independent or time-dependent killing and produces moderate to prolonged postantibiotic eﬀects [29]. Thus, one would predict that 24-hr AUC/MIC would be the important PK/PD parameter determining eﬃcacy. However, there are no animal or human studies speciﬁcally designed to characterize the pharmacodynamics of this drug combination. Nevertheless, eradication rates in otitis media and sinusitis due to S. pneumoniae and H. inﬂuenzae using a double-tap methodology were very high (88–100%) for susceptible strains and very low (27–50%) for resistant strains [30,31]. Clinical trials in developing countries with trimethoprim-sulfamethoxazole for community-acquired pneumonia in children have demonstrated the drug’s equivalent eﬃcacy to penicillin, ampicillin, and chloramphenicol

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[32,33]. In one clinical trial in Pakistan, trimethoprim-sulfamethoxazole was less eﬀective than amoxicillin in severe pneumonia [34]. However, there was no correlation of outcome with the presence or absence of trimethoprimsulfamethoxazole resistance in S. pneumoniae. It is possible that the high respiratory tract concentrations of trimethoprim maintained some eﬃcacy even in the presence of resistant strains. VANCOMYCIN Vancomycin is used primarily in severe community-acquired pneumonia, often with other agents. The drug is added to ensure eﬀective therapy even against multiple drug-resistant S. pneumoniae. Such strains are still 100% susceptible to vancomycin at concentrations of 0.5 Ag/mL or less. Vancomycin is not active against H. inﬂuenzae, M. catarrhalis, and atypical pathogens. Vancomycin is a very water-soluble drug and penetrates poorly into respiratory secretions. Mean epithelial lining ﬂuid concentrations have ranged from 10% to 18% of serum concentrations [35,36]. Penetration was higher in patients with lung inﬂammation (25%) than in patients without inﬂammation (14%) [36]. Thus, one needs vancomycin serum concentrations of 15–20 Ag/mL to ensure ELF levels of 2 Ag/mL. A variety of pharmacodynamic studies have been performed with vancomycin. In a murine peritoneal infection with S. pneumoniae, the peak level and AUC were both important for eﬃcacy [37]. Studies in the murine thigh-infection model found that the AUC was the major determinant of in vivo eﬃcacy [25]. The magnitude of the peak/MIC and the 24-hr AUC/MIC required for eﬃcacy were 5.7 and 6.4 for free drug, respectively [37]. However, Moise et al. [38] found in patients with ventilator-acquired pneumonia due to S. aureus that the 24-hr AUC/MIC required for clinical and bacteriologic cure was 345 and 850, respectively. These higher 24-hr AUC/MIC targets in the pneumonia model are likely due to both the protein binding of vancomycin and its poor penetration into respiratory secretions. Because the MICs for vancomycin against S. pneumoniae are about four-fold lower than for S. aureus, current dosages of 1 g twice daily should provide adequate concentrations in ELF for most strains. On the other hand, S. aureus infections will likely require higher concentrations to ensure that concentrations above the MIC are maintained in ELF. Continuous infusion of vancomycin has been recommended to maintain constantly adequate concentrations of vancomycin in ELF for most strains of S. aureus. LINEZOLID Linezolid is the ﬁrst oxazolidinone approved for treatment of communityacquired pneumonia [39,40]. The drug is active against S. pneumoniae, H.

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inﬂuenazae, M. catarrhalis, and atypical pathogens. Linezolid is also active against penicillin-, macrolide, and quinolone-resistant strains of S. pneumoniae. The drug has excellent bioavailability and is available for both oral and intravenous administration. However, the cost of the drug precludes its routine use in community-acquired pneumonia. Linezolid diﬀers from vancomycin in that the drug has enhanced penetration into respiratory secretions. Epithelial lining ﬂuid concentrations are about three-fold higher than simultaneous concentrations in serum [41]. The pharmacodynamics of linezolid against S. pneumoniae and S. aureus has been studied in the murine thigh-infection model [42]. The 24-hr AUC/MIC is the PK/PD parameter determining eﬃcacy of the drug. The magnitude or target required for eﬃcacy ranged from 22 to 97 for multiple strains of both organisms. A dose of linezolid at 600 mg b.i.d. would provide a 24-hr AUC/ MIC value in serum of 120 for organisms with MICs of 1 Ag/mL. Because ELF concentrations are signiﬁcantly higher, linezolid should be very eﬀective for treatment of S. pneumoniae and S. aureus pulmonary infections. Clinical trials of linezolid have demonstrated superior activity to ceftriaxone in pneumococcal pneumonia with bacteremia and superior activity to vancomycin for MRSA in ventilator-acquired pneumonia [40,43]. The drug has also been eﬀective in eradicating penicillin-resistant pneumococci from the middle ears of gerbils and chinchilla [44,45]. However, linezolid was not eﬀective in eradication of H. inﬂuenzae [45].

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19. Hitt JA, Gerding DN. Sputum antimicrobial levels and clinical outcome in bronchitis. Semin Respir Infect 1991; 6:122–128. 20. Rodvold KA, Gotfried MH, Danziger LH, Servi RJ. Intrapulmonary steadystate concentrations of clarithromycin and azithromycin in healthy adult volunteers. Antimicrob Agents Chemother 1997; 41:1399–1402. 21. Biermann C, Loken A, Riise R. Comparison of spiramycin and doxycycline in the treatment of lower respiratory infections in general practice. J Antimicrob Chemother 1988; 22(suppl B):155–158. 22. Harazim H, Wimmer J, Mittermayer HP. An open randomized comparison of oﬂoxacin and doxycycline in lower respiratory tract infections. Drugs 1987; 34(suppl 1):71–73. 23. Norby SR, the Nordic Atypical Pneumonia Study Group. Atypical pneumonia in the Nordic countries: aetiology and clinical results of a trial comparing ﬂeroxacin and doxycycline. J Antimicrob Chemother 1997; 39:499–508. 24. Teixeira LR, Sasse SA, Villarino MA, Nguyen T, Mulligan ME, Light RW. Antibiotic levels in empyemic pleural ﬂuid. Chest 2000; 117:1734–1739. 25. Craig WA. Pharmacokinetic/pharmacodynamic parameters: rationale for antibacterial dosing of mice and men. Clin Infect Dis 1998; 26:1–12. 26. Christianson J, Andes D, Craig WA. Characterization of the pharmacodynamics of clindamycin against Streptococcus pneumoniae in a murine thighinfection model. 41th Interscience Conference on Antimicrobial Agents and Chemotherapy, American Society for Microbiology, 2001. 27. Schreiner A. Use of clindamycin in lower respiratory tract infections. Scand J Infect Dis 1984; 43:56–61. 28. Dubar V, Lopez I, Gosset P, Aerts C, Voisin C, Wallaert B. The penetration of co-trimoxazole into alveolar macrophages and its eﬀect on inﬂammatory and immunoregulatory functions. J Antimicrob Chemother 1990; 26:791–802. 29. Gudmundsson S, Craig WA. Postantibiotic eﬀect. In: Lorian VL, ed. Antibiotics in Laboratory Medicine: Williams & Wilkins, 835–899. 30. Harmory BH, Sande MA, Sydnor A, Seale DL, Gwaltney JM. Etiology and antimicrobial therapy of acute maxillary sinusitis. J Infect Dis 1979; 139:197– 202. 31. Leiberman A, Leibovitz E, Piglansky L, Raiz S, Press J, Yagupsky P, Dagan R. Bacteriologic and clinical eﬃcacy of trimethoprim-sulfamethoxazole for treatment of acute otitis media. Pediatr Infect Dis J 2001; 20:260–264. 32. Campbell H, Byass P, Forgie IM, O’Neill KP, Lloyd-Evans N, Greenwood BM. Trial of co-trimoxazole versus procaine penicillin with ampicillin in treatment of community acquired pneumonia in young Gambian children. Lancet 1988; 8621:1182–1184. 33. Mulholland EK, Falade AG, Corrah PT, Omosigho C, N’Jai P, Giadom B, Adegbola RA, Tschappeler H, Todd J, Greenwood BM. A randomized trial of chloramphenicol vs. trimethoprim-sulfamethoxazole for the treatment of malnourished children with community acquired pneumonia. Pediatr Infect Dis J 1995; 14:959–965. 34. Straus WL, Qazi SA, Kundi Z, Nomani NK, Schwartz B. Antimicrobial re-

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9 Acute Community-Acquired Rhinosinusitis James A. Hadley University of Rochester Medical Center Rochester, New York, U.S.A.

INTRODUCTION Acute and chronic rhinosinusitis represent some of the most prevalent disorders encountered by physicians in ambulatory care environments and are among the most common diagnoses for which antibiotics are prescribed [1,2]. The high prevalence of this disease accounts for a large contribution of health-care resource consumption and costs, and yet the incidence of this disorder seems to be increasing [3,4]. Because the etiology and pathophysiology remain obscure, rhinosinusitis poses a considerable challenge for physicians in the overall management of the problem. Sinus disease remains one of the most common reasons for antimicrobial prescriptions in the United States. Data from the National Ambulatory Medical Care Survey [5] show that sinusitis is the ﬁfth most common diagnosis for which antibiotics are prescribed. Health-care expenditures attributable to a primary diagnosis of acute or chronic rhinosinusitis were estimated to be $3.39 billion in 1996. Treatment has traditionally been based on empiric data aimed at the most common pathogens (i.e., Streptococcus pneumoniae, Haemophilus inﬂuenzae, and Moraxella catarrhalis), and prescriptions for broad-spectrum anti155

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microbials have generally been utilized [6]. Due to prior overuse of these agents, the development of resistant bacteria has become a problem. Streptococcus pneumoniae remains the most important pathogen, and it has steadily acquired resistance to a majority of the currently available antibacterial agents. Although the majority of these infections are mild and are community acquired during the respiratory season, they often lead to signiﬁcant morbidity and loss of productivity in school or work environments. The disruption of the patient’s quality of life from the symptoms leads these patients to seek early medical management. In addition, this health-care problem has been increasing in incidence and consequently poses a major economic burden. Rhinosinusitis is a complex disease and the management of the disorder is controversial. Even though the majority of these infections begin as viral upper respiratory diseases, patients demand antimicrobial therapy for fear of developing the more serious complications of this disorder. Antibiotic therapy is most often administered empirically without factual knowledge of the type of pathogen potentially causing the infection. Injudicious usage and indiscriminate prescription of antibiotics has fostered the rapid development of antibiotic-resistant organisms over the past two decades. Appropriate medical management of this common problem requires a systemic approach to the diagnosis, reasonable and swift management, and the considerations of adjunctive medical therapy. Deﬁnition of rhinosinusitis: Acute community-acquired rhinosinusitis is most often preceded by a common viral upper respiratory tract infection. Common cold symptoms are characterized by sneezing, rhinorrhea, nasal congestion, facial pressure, postnasal drip, cough, sore throat, fever, and myalgia. Bacterial superinfection may occur at any time during the course of this viral infection. The term sinusitis is used to describe any inﬂammatory response involving the sinus cavities with resultant clinical symptoms. In 1996, the American Academy of Otolaryngology–Head and Neck Surgery (AAO-HNS) Task Force for Rhinosinusitis developed working deﬁnitions of this disorder in order for health-care providers to communicate appropriately regarding this disease [7]. The term rhinosinusitis was found to be more appropriate than sinusitis alone because the mucous membranes of the nasal passages and paranasal sinuses are contiguous and are histologically identical, and infection or inﬂammation of the sinus cavities is commonly preceded by rhinitis [7]. Infection of the sinus cavities alone is rare. Rhinosinusitis, then, can be clinically deﬁned as an inﬂammatory response involving the mucous membranes of the nasal cavity and paranasal sinuses, the ﬂuids within these cavities, and the underlying bone.

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Acute community-acquired bacterial rhinosinusitis (ABRS) is an inﬂammatory event that is the result of bacterial infection within the sinus cavities and commonly follows an acute upper respiratory viral episode. Recent guidelines for the medical management of this disorder have been established by the Sinus and Allergy Health Partnership [1]. Because of the high rates of respiratory infections and bacterial resistance, this group established bacterial eﬃcacy rates and used mathematic modeling to develop a rational algorithm for the treatment of this very common disorder. Chronic rhinosinusitis (CRS) remains poorly deﬁned. Although many articles describe therapeutic measures for CRS, there are no established characteristics of the symptoms of this entity [8]. In fact, the Federal Drug Administration does not consider this diagnosis when planning medication trials. CRS has been characterized as an inﬂammation and infection of the sinus cavities, which is deﬁned by the length of time of the patient’s symptoms (longer than 3 months). Still, the pathophysiology and pathology of CRS remain somewhat indeterminate. EPIDEMIOLOGY According to national governmental statistics, 32 million persons were told they had sinusitis in 1997 [4], and 16.3% of the United States population over the age of 18 had sinusitis. These rates were highest among women and people living in the South. The number of physician visits annually reached 11.7 million for this diagnosis in the year 2000. Hospital outpatient visits totaled 1.2 million in the same year [9]. The development of acute community-acquired rhinosinusitis is related to a series of environmental and host factors [7]. These are listed in Table 1. Not all patients present with a similar cause, and a variety of factors may coexist in any given patient. There are many risk factors, and these may be associated with viral infections, distorted nasal and sinus anatomy, and allergic and nonallergic rhinitis. In essence, there are multiple and various causes of rhinosinusitis, and many diﬀerent factors may be present, which makes it diﬃcult to determine the precise cause in any given patient. Host factors, genetic predisposition, cystic ﬁbrosis, allergic/immune conditions, anatomic abnormalities, endocrine and metabolic disorders, environmental causes, infectious/viral agents, chemicals, medications, and surgery or trauma are all included in the etiology. ETIOLOGY In the United States, adults will experience an average of two to three, and children will experience six to eight, viral respiratory illnesses annually [9].

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TABLE 1 Multifactorial Causes of Rhinosinusitis Environmental factors Infectious/viral agents Trauma Noxious chemicals (occupational exposure) Iatrogenic Medications Surgery Host Factors Genetic/congential conditions Cystic fibrosis Immotile cilia syndrome Allergic/immune conditions Anatomic abnormalities Systemic diseases Endocrine Metabolic Neuromechanisms Neoplasm Source: Ref. 7.

Viral rhinosinusitis for the most part is self-limiting, and symptoms normally improve within 5–7 days. Secondary bacterial infection may occur at any time throughout the course of a viral infection and may complicate approximately 2% of cases of viral rhinosinusitis. Community-acquired acute rhinosinusitis, then, is the development of a bacterial infection that follows inﬂammation of a viral episode, the sinus cavities being colonized with bacterial pathogens common to the community. Studies involving direct cultures of the maxillary antrum during both acute and chronic infections demonstrate the typical bacterial responsible for the infections. Maxillary sinus aspirations performed under controlled circumstances demonstrate contamination by Streptococcus pneumonia, Haemophilus inﬂuenzae, and other bacteria, including Moraxella catarrhalis, as the prevalent pathogens in acute bacterial rhinosinusitis. These pathogens have been investigated by many authors [10] (see Table 2). The bacteria responsible for chronic rhinosinusitis are somewhat diﬀerent; although Streptococcus pneumonia remains a pathogen, other bacteria include anaerobic pathogens and Staphylococcus species [11–13].

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TABLE 2 Common Pathogens in Acute Maxillary Rhinosinusitis Bacterial species/positive cultures in 383 pretreatment sinus aspirates Strep pneumococcus H. influenzae Anaerobes Strep. species Moraxella catarrhalis Staph. aureus Others

41% 35% 7% 7% 3.5% 3.0% 3.5%

Source: Ref. 11.

PATHOGENESIS

The development of acute community-acquired rhinosinusitis involves damage to the integrity of the mucosa and/or ostial obstruction, which then predisposes the paranasal sinuses to infection from bacteria. Normal Anatomy and Physiology In order to understand the physiology of infection, it is helpful to review the normal physiology and anatomy of the paranasal sinuses. The paranasal sinuses represent paired, air-ﬁlled cavities in the mid-face that are lined with respiratory mucosa. With the exception of the sphenoid sinus, the paranasal sinuses arise as evaginations from the nasal cavity, developing mostly after birth. The various ostia of the sinuses drain into the nasal cavity and potentially can become obstructed. The maxillary sinus is the largest, and its ostia drains into the lateral nasal wall under the middle nasal turbinate. The ethmoid sinuses are the most complex; they represent a group of small sinus cavities that may vary greatly in number and are believed to represent the origin of the majority of paranasal sinus diseases. The anterior ethmoid sinuses drain into the middle meatus, under the middle turbinate. The posterior ethmoid sinuses usually drain into the spheno-ethmoid recess posteriorly. The frontal sinuses vary greatly in size and are usually only secondarily involved in acute respiratory tract infections. The sinuses drain into the anterior nasal-fronto-ethmoid recess. (See Figs. 1 and 2.) The mucosa of the nasal cavity and the paranasal sinuses represents a continuum of the mucosa of the respiratory tract. This mucosa is a ciliated, pseudostratiﬁed, columnar epithelium, and it also contains mucosal glands

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FIGURE 1 Front view of paranasal sinuses demonstrating narrow pathways and relationship of drainage from maxillary sinus into nasal cavity.

and goblet cells. The goblet cells and mucosal glands produce the mucus and serous layers of the mucous blanket that lines this epithelium. The cilia move the mucus gradually to the natural ostia of the paranasal sinus cavities and then into the nasopharynx. Nasal mucus has numerous functions and represents the means of humidiﬁcation, warming of air, and ﬁltration of inspired air, the important roles of the nasal cavities. Nasal mucus also is involved in the immune defense of the upper respiratory tract: not only does it contain inﬂammatory cells, it also provides inﬂammatory chemical mediators that upregulate and modify the immune response. The function of the cilia is to gradually sweep the nasal mucus toward the natural sinus ostia. Normal ciliary function results in clearance of the sinus cavities within a short period of time. Normal transport time from the front of the nose to the posterior nasopharynx is approximately 20 min. Cilia stasis may occur or during the acute inﬂammatory reaction, or may be in-

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FIGURE 2 Cut view of paranasal sinuses showing normal mucociliary clearance on one side and obstruction secondary to inflammatory blockage on the other side of the paranasal sinuses. It is clear that the narrow drainage pathways lead to a potential for obstruction and stasis of secretions. (Courtesy CIBA-Geigy collection.)

duced by other toxic agents. With a decrease in ciliary function, the normal nasal mucus stagnates and forms a nidus for secondary infection. Mucous stasis and obstruction of the ostia may allow decreased oxygenation within the paranasal sinus cavities. The lowered oxygen tension favors the development of bacterial secondary infection. Gas exchange within the obstructed sinus cavities is inhibited, and this may favor the growth of bacteria in an anaerobic environment. With obstruction of the sinus ostia, there is a transient decrease in the pressure within the large sinus cavities. Transudation results from the lowered pressure and may lead to signiﬁcant edema, bleeding, and sinus pain. The initial decrease in partial pressure within the sinus cavity may be followed by an increase in pressure from the development of the secondary infection causing pressure on the sinus cavity walls. These pressure diﬀerentials may explain the facial discomfort experienced by persons who are descending from altitudes or deep sea diving [14].

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FIGURE 3 Vicious cycle of respiratory infections. (From Ref. 16)

Pathophysiologically, the inﬂammation from an inciting event causes swelling with the narrow drainage pathways of the sinuses. A partial or total obstruction of the ostia induces stagnation and stasis of the normal mucus, which then serves as a medium for the growth of resident pathogenic bacteria. Inﬂammatory mediators are liberated and lead to the development of patient symptoms. A vicious cycle may then develop as a result of continued mediator release. (See Fig. 3 [16].) Antimicrobial therapy is usually indicated to resolve the inﬂammatory cascade and break this vicious circle. Once appropriate antibiotics and other anti-inﬂammatory measures are instituted, there is usually complete healing and resolution of symptoms.

CLINICAL MANIFESTATIONS In clinical practice, the diagnosis of acute community-acquired rhinosinusitis is based on patient symptoms and potential ﬁndings on physical examination [15]. Too often, however, the clinical ﬁndings are diﬃcult to determine on every presentation, and diﬀerentiation from viral rhinosinusitis and bacterial rhinosinusitis is challenging without culture data. The signs and symptoms, as deﬁned by the Task Force on Rhinosinusitis, include facial pain/pressure, facial congestion/fullness, nasal obstruc-

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tion, nasal/postnasal discharge, hyposmia/anosmia, fever, halitosis, fatigue, dental pain, cough and otalgia [16]. Acute community-acquired rhinosinusitis typically manifests itself as an upper respiratory tract infection that persists beyond 5–7 days, and the patient has persistent symptoms lasting longer than ten days. A patient’s symptoms of nasal congestion and postnasal discharge that last only a few days are more characteristic of a viral disorder, such as a rhinovirus or an adenovirus. A common misconception is that the presence of discolored nasal secretions predictably indicates a bacterial infection. Patients with viral infections and chronic rhinitis alone may also have discolored nasal discharge, and the diagnostic speciﬁcity of discolored nasal discharge was reported to be only 52% [17]. A broad deﬁnition of the clinical symptoms incorporates the following (see Table 3): Percussion of the sinuses in addition to the presence of other factors may also assist the clinician in predicting the presence of an acute infection. Increased maxillary facial pain and pressure while the patient bends the head forward may be another positive sign. The diagnosis of acute community-acquired rhinosinusitis in children is more diﬃcult. Children experience up to six or more episodes of viral upper respiratory tract infections per year, and these may take longer to resolve. The incidence of viral infections is greater among children attending day-care or school [1]. The symptoms are similar to the adult major and minor factors, but children demonstrate persistent rhinorrhea of a mucopurulent nature and can develop an associated nocturnal cough. Symptoms of rhinosinusitis in TABLE 3

Clinical Symptoms of Acute Community-Acquired Rhinosinusitis

Major symptoms Facial congestion/fullness Nasal discharge/purulence/discolored nasal discharge Facial pain/pressurea Nasal obstruction/blockage Hyposmia/anosmia Fever (acute rhinosinusitis only)b a

Minor symptoms Headache Halitosis Dental Pain Ear pain/fullness/pressure Fever Fatigue Cough (in children)

Facial pain/pressure alone does not constitute a suggestive history of acute rhinosinusitis in the absence of another major sign or symptom. b Fever in acute rhinosinusitis alone does not constitute a suggestive history of acute rhinosinusitis in the absence of another major sign or symptom. Source: Ref. 7.

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children usually consist of a ‘‘cold’’ lasting more than 10 days, sometimes associated with low-grade fever; thick, yellow-green nasal discharge; headache, irritability, or fatigue [18,19]. Foul-smelling nasal discharge and halitosis are common ﬁndings with poor resolution despite at-home remedies. Early recognition and appropriate management are extremely important in prevention of the more serious complications of rhinosinusitis. Sinus infection may potentially spread to the orbit and meninges either by direct extension or by venous thrombophlebitis. Direct and immediate referral to an otolaryngologist in warranted in immunocompromised patients with serious sinus symptoms or impending signs of orbital cellulitis. Diagnostic Modalities Physical examination of the patient usually provides little information to assist the clinician in the diagnosis. The clinical diagnosis of acute communityacquired rhinosinusitis is also clouded by the lack of uniformity among physicians in regard to classiﬁcation of the disease. There are many professionals involved in the diagnosis and management of this disease, including primary care physicians, otolaryngologists, pediatricians, and other specialists. A number of diagnostic techniques, however, can assist the clinician in determination of the presence of community-acquired rhinosinusitis. Anterior Rhinoscopy An evaluation of the anterior nasal chamber, the nasal turbinates, and perchance the middle meatus with either a nasal speculum (see Fig. 4) or an oto-

FIGURE 4 View of anterior rhinoscopy with nasal speculum demonstrating relationship of inferior and middle turbinates. (Courtesy R. Netter Collection.)

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scope may document turbinate swelling, mucopurulent nasal secretions, and purulence stemming from the sinus drainage pathways. A thorough examination of this area is helpful in determining the presence or absence of clinical disease [15]. Diagnostic nasal endoscopy is the method favored by otolaryngologists in the diagnosis of disorders of the nose and sino-nasal tract and is the primary evaluation strategy for patients with recurrent or chronic symptoms. Nasal endoscopy employs the use of rigid or ﬂexible nasal endoscopes to examine the entire nasal cavity and may allow microbiologic culture [13]. Systemic nasal endoscopy can demonstrate the normal sinus drainage pathways or show aberrant anatomy and active mucopurulent secretions (see Fig. 5). Direct culture of purulent secretions from the area of the middle meatus has been demonstrated to correlate with cultures obtained directly from the maxillary sinuses [20,21]. Transillumination This technique is no longer utilized widely: it is subject to operator variability and does not diﬀerentiate bacterial from viral infection. Ultrasound Not widely used, and subject to false-negative results, ultrasonography uses acoustic imaging to detect reﬂection of sound waves oﬀ two media with

FIGURE 5 View of a nasal endoscope which can visualize the entire nasal cavity.

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diﬀering acoustic characteristics. This technique may be used to help follow the course of the disease, especially in frontal or maxillary sinus disease. Radiography Plain x-ray evaluation of the sinuses was once the diagnostic procedure of choice but has been recently shown to provide an inaccurate assessment of the extent of sinus inﬂammation [22]. Air-ﬂuid levels and opaciﬁcation may enhance the diagnosis of acute rhinosinusitis in the patient with acute symptoms. As an adjunct to diagnosis, plain x-rays are helpful but should not be utilized as the sole criteria for selecting methods of treatment (see Fig. 6). Computed Tomography (CT) Considered the gold standard for imaging of paranasal sinuses, CT scans are particularly useful for displaying the extent of the inﬂammation, which may be missed by nasal endoscopy. This technique is extremely sensitive, but lacks speciﬁcity because many viral infections may also produce CT abnormalities [22]. However, recommendations are made to consider CT scans in patients who fail to respond to adequate medical management after appropriate medical therapy. In addition, they are recommended in face of any impending complication of infection of the sinuses (see Fig. 7).

FIGURE 6 Radiograph of Water’s view of paranasal sinuses and air-fluid level on left.

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FIGURE 7 CT scan of anterior nasal sinuses which demonstrates opacification of maxillary and partial ethmoid sinuses on the right and air-fluid level on the left.

The use of CT scans in community-acquired rhinosinusitis should be limited. MRI Scan The imaging provided by magnetic resonance demonstrates excellent visualization of the soft tissue, but little information regarding the cortical bone. MRI scans are useful for evaluation of regional and intracranial complications of infection prior to surgical and medical management. Culture Techniques The routine use of nasal cultures in identifying the cause of bacterial rhinosinusitis has not proved useful, due to lack of reliability. The paranasal sinuses are relatively inaccessible and thus microbiological specimens are diﬃcult to obtain. The maxillary sinus (antral) tap has been the recommended approach, and samples are sent for culture for both aerobic and anaerobic pathogens (see Fig. 8). Nasal endoscopic cultures, however, have been shown to correlate well with ﬁndings on maxillary sinus tap [20,23] (see Fig. 9).

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FIGURE 8 Transmaxillary aspiration through the nasal cavity at the level of inferior meatus. This is the ‘‘gold-standard’’ of maxillary sinus culture study.

FIGURE 9 Nasal endoscopic view of swab taking a culture through the nose at the level of the maxillary sinus drainage pathway.

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Temporal Aspects of Rhinosinusitis The typical progression of acute community acquired rhinosinusitis may proceed along one of four scenarios: complete resolution without aftereﬀects, development of adverse sequelae, transition to symptomatic chronic rhinosinusitis, or development of silent chronic rhinosinusitis. In order to facilitate the diagnosis and treatment of acute community acquired rhinosinusitis, deﬁnitions based on the temporal nature of the disease were developed and subsequently adopted by the Agency for Healthcare Research and Quality [16,24] (see Table 4). Acute Adult Rhinosinusitis This is the most common presentation and is usually characterized by the worsening of symptoms after 5–7 days and then persistence of major or minor factors for at least 10 days. The symptoms resolve completely after 4 weeks. Common denominators of the positive history include facial pain, pressure, and purulent nasal discharge that persist after a common viral episode. Subacute Adult Rhinosinusitis The continuum of symptoms, or the progression of symptoms after 4 weeks and lasting up to 12 weeks, deﬁnes this form of rhinosinusitis. Patients may not have been managed appropriately during the acute stage, or the symptoms may have been not severe enough to warrant antimicrobial therapy. This stage usually resolves completely after eﬀective medical management. Recurrent Acute Adult Rhinosinusitis The symptoms are the same as those of adult rhinosinusitis, but the patient may experience up to four episodes in a year. The symptoms usually completely resolve between episodes. Antimicrobial therapy is not generally required during the interim.

TABLE 4

Temporal Aspects of Rhinosinusitis

Acute Lasts up to 4 weeks, with total resolution of symptoms Nasal discharge/purulence/discolored postnasal drainage Subacute Lasts longer than 4 weeks but less than 12 weeks Recurrent Acute 4 or more episodes per year, with resolution in between attacks Chronic 12 weeks or more of signs/symptoms Source: Ref. 7.

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Chronic Adult Rhinosinusitis Chronic rhinosinusitis occurs when symptoms last 12 or more weeks. Patients may experience acute exacerbations with sudden worsening of the baseline symptoms, or the development of new symptoms during this stage. COMPLICATIONS Untreated acute community-acquired rhinosinusitis may potentially lead to severe, and perhaps fatal, complications. Rhinosinusitis may spread to important neighboring structures, including the eye, with development of periorbital cellulititis, subperiosteal abscess, orbital cellulititis, or orbital abscess and blindness (see Fig. 10). Severe intracranial complications may occur such as meningitis and brain abscess, primarily from ethmoid and frontal sinus infection. Patients with impending complications require immediate

FIGURE 10 CT scan of patient with acute rhinosinusitis on the left which has progressed to involve the orbit and formation of an abscess of the orbit.

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treatment and referral to appropriate specialists. Aggressive itravenous antibiotics and hospitalization are required. Clinical signs of complications include symptoms of sepsis—chills, high fever, severe headache, excessive eyelid swelling, chemosis or proptosis of the eye, or restriction of ocular movement. Aﬀected patients require urgent consultation with an otolaryngologist for appropriate management of their impending complications and potential immediate surgical drainage of the infection.

MANAGEMENT The main strategy of management of acute community-acquired rhinosinusitis resolves around relief of symptoms and eradication of the underlying cause of the infection. The goals are to reduce the inﬂammation and tissue swelling, promote sinus drainage and maintain the ostia of the normal sinus drainage pathways. Treatment regimens should interrupt the pathologic vicious circle that can lead to recurrent infection, complications, or development of chronic rhinosinusitis. Antimicrobial Management Acute community-acquired rhinosinusitis is managed with antimicrobials directed against the common pathogens involved in the infection. The organisms have changed little over the past 50 or more years. Streptococcus pneumoniae and Haemophilus inﬂuenzae are the predominant pathogens and make up more than 70% of all bacterial species isolated [10,25]. Moraxella catarrhalis is another causative pathogen, but its clinical impact remains limited because infection with this pathogen tends to resolve spontaneously. Bacterial resistance has become a major problem in the treatment of these infections over the past decade. The reader is referred to the other chapters in this book regarding this problem. Suﬃce it to say that the empiric choice of an antimicrobial is no longer recommended. The clinician needs to recognize the potential for resistant bacteria and choose an appropriate antibiotic that will be eﬀective in killing the responsible pathogen (see Table 5). The Sinus and Allergy Health Partnership recently developed guidelines as an educational tool for clinicians who are involved in treating patients with acute bacterial rhinosinusitis [1] (see Table 6). The objective was to provide a systematic approach for the diagnosis and management of this disorder. Antimicrobial selection is now based on consideration of a bacterial eﬃcacy model. The Poole therapeutic model [26] was introduced as a mathematical method for determination of the eﬃcacy of a chosen antimicrobial. Based on patient distribution, pathogen distribution, spontaneous resolution

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TABLE 5

Hadley Antimicrobials for Rhinosinusitis

Fluoroquinolones (95%) HD Amoxicillin/clavulanate (94%) Amoxicillin/clavulanate (91%) HD Amoxicillin (88%) Cefpodoxime proxetil (85%) Cefdinir (85%) Cefixime (83%) Cefuroxime axetil (82%) TMP/SMX (78%) Macrolides (72%) Placebo (60%)

E

jz

More effective, More antibiotic use

Less effective, Less antibiotic use

rate, and the resolution based on current susceptibility data for each organism at pharmacokinetic/pharmacodynamic breakpoints, we can calculate an estimated eﬃcacy for any given antimicrobial therapy. Considerations utilized in the development of the treatment guidelines included patient age, severity of disease, prior use of antibiotics, and the relative rank order of predicted eﬃcacy. Antimicrobial therapy thus can be placed into a relative rank order of predicted eﬃcacy in adult patients with community-acquired acute bacterial rhinosinusitis. Antimicrobials showing a greater than 90% eﬃcacy include amoxicillin/clavulanate, and the ﬂuoroquinolones. Those showing 80–90% eﬃcacy include high-dose amoxicillin, cefdinir, cefuroxime axetil, and cefpodoxime proxetil. Antibiotics showing 70–80% resolution include clindamycin (based on gram-positive coverage only), cefprozil, azithromycin, clarithromycin, and erythromycin. Based on the fact that the predicted spontaneous resolution rate in untreated adults with acute bacterial rhinosinusitis is 46.6%, recommendations to use other antimicrobials are not justiﬁed based on this eﬃcacy data. Amoxicillin remains eﬀective for penicillin-intermediate and -resistant Streptococcus pneumoniae but is less eﬀective against h-lactamase producing organisms. Addition of clavulanic acid with amoxicillin provides coverage against all three important pathogens in acute bacterial rhinosinusitis. Second-generation cephalosporins have adequate activity against penicillin-intermediate Streptococcus pneumoniae, Haemophilus inﬂuenza, and Moraxella catarrhalis but have limited activity against penicillin-resistant Streptococcus pneumoniae. Trimethoprim/sulfamethoxazole and the macrolides have limited indications in the treatment of acute bacterial rhinosinusitis. Increasing resistance to Streptococcus pneumoniae has limited their use for upper respiratory tract infections. Clindamycin remains eﬀective against

No

# Yes

Moderate

Moderate

#

#

Yes OR

Mild OR

#

#

# No

Prior antibiotics

86.7 84.4

Cefpodoxime/cefdinir Cefuroxime h-Lactam allergic: TMP/SMX, Doxycycline, Macrolide Amoxicillin/clavulanate Amoxicillin

Cefpodoxime/cefdinir Cefuroxime h-Lactam allergic: Fluoroquinolone Fluoroquinolone Amoxicillin/clavulanate Combination

93.3 88.8

Amoxicillin/clavulanate* Amoxicillin*

95.1 94.4

86.7 84.4

93.3 88.8

Predicted efficacy (% of patients)

Initial therapy

Suggested Antimicrobials for Adult Rhinosinusitis

Mild

Severity

TABLE 6

Reevaluate patient Fluoroquinolone, reevaluate patient Fluoroquinolone, reevaluate patient

Amoxicillin, clindamycin, fluoroquinolone Amox/clav, fluoroquinolone, combination Reevaluate patient

Fluoroquinolone; reevaluate patient Amox/clav, fluoroquinolone, cefpodoxime, cefixime

Fluoroquinolone; reevaluate patient Amox/clav, fluoroquinolone, cefpodoxime, cefixime Amoxicillin, clindamycin, fluoroquinolone Amox/clav, fluoroquinolone, combination Fluoroquinolone, combination

Switch options

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gram-positive pathogens and certain anaerobes, but it is ineﬀective against the majority of gram-negative pathogens. Ancillary Management Ancillary therapy should enhance the drainage of the infected sinus cavities and help relieve facial pain, pressure, nasal congestion, postnasal discharge, and the other systemic symptoms. Nonpharmacologic therapy is indicated for patients with acute community acquired rhinosinusitis as an adjunct to antibiotic management. The adjunctive use of topical nasal saline has been shown to have signiﬁcant impact in reduction of the tenacity and thickness of the nasal and sinus secretions. In addition, household remedies such as the use of steam-tents may also give patients some relief. Hypertonic saline has been shown to increase mucociliary clearance and ciliary frequency, as well as mucociliary transit times of saccharin [27,28]. The use of hypertonic saline in children was associated with statistically signiﬁcant improvement in symptoms compared with nasal saline alone. Adjunctive pharmacologic therapy may include the use of topical nasal decongestants. To avoid rebound rhinitis, it is recommended that the patient use these topical decongestants for less than 5 to 7 days. Antihistamine therapy is not usually recommended, although patients who have a signiﬁcant history of inhalant upper respiratory allergies may potentially use these medications in a preventive fashion. Mucolytic therapy with the use of guaifenesin has also been shown to give some beneﬁt. Patients may actually feel some relief with a guaifenesin/pseudoephedrine combination product. Although intranasal steroids are currently not indicated in cases of acute bacterial rhinosinusitis, their theoretic value lies in their ability to decrease inﬂammation. Topical nasal corticosteroid therapy has been both discouraged and recommended for adjunctive therapy. An investigation of children diagnosed with acute bacterial rhinosinusitis reported improvement in a group that used intranasal budesonide compared with a group receiving oral pseudoephedrine [29]. Topical intranasal steroids have a marked antiinﬂammatory action that decreases vascular permeability and inhibits the release of chemical mediators, especially histamine, leukotrienes, and others. They reduce the cellular inﬂux to the inﬂammatory sites and modify both the early-phase and the late-phase response in inﬂammatory rhinitis. Topical nasal steroids are advocated for patients with hyperplastic polypoid rhinosinusitis [30]; these drugs reduce polyp inﬂammation but unfortunately they do not reduce the expression of pro-inﬂammatory cytokines. Combination therapy with systemic steroids and topical intranasal steroids has a dramatic increase in eﬀect, but unfortunately it does not change the need for consideration of surgical intervention [31].

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Oral systemic corticosteroids are extremely eﬀective in reducing the inﬂammation secondary to rhinosinusitis. They dramatically reduce the edema from increased capillary permeability and reduce the cellular inﬂux. These medications are generally not recommended in cases of acute bacterial rhinosinusitis. The potential risk of development of a more fulminant infection suggests that their use be reserved for more chronic disease states. Leukotriene receptor antagonists have also been recently advocated for consideration of therapy in patients with rhinosinusitis. These medications are perhaps better suited to patients with the more chronic forms of inﬂammation rather than patients who have an acute bacterial infection. Role of Surgery Surgical intervention for acute bacterial sinus infections generally is reserved for patients with recurrent acute or chronic rhinosinusitis who have not responded to appropriate medical therapy, or in cases where there is a potential for the development of an acute complication. There are more than 150,000 sinus surgeries performed per year in the United States. However, surgery is not recommended for the typical case of acute communityacquired rhinosinusitis. Most surgical procedures are performed on patients with complications of the disorder or other forms of rhinosinusitis, including extensive nasal polyposis, or chronic rhinosinusitis with persistence of abnormal ﬁndings on CT scans. Endoscopic sinus surgery theoretically aims to restore the natural drainage patterns of the paranasal sinuses, open the blocked ostiomeatal complex, and allow for drainage of the anterior ethmoid cells. This ‘‘functional’’ surgical technique is used to restore the mucociliary clearance and ventilation through the ostia. Computer-assisted sinus surgery now also allows for precise identiﬁcation of areas within the sinuses and may be useful for

TABLE 7

Absolute Indications for Surgery in Adult Rhinosinusitis

Bilateral extensive and massive obstructive nasal polyposis with complications Complications of adult rhinosinusitis Subperiosteal or orbital abscess Meningitis Brain abscess Chronic adult rhinosinusitis with mucocele or mucopyocele formation Invasive or allergic fungal adult rhinosinusitis Diagnosis of tumor of nasal cavity and paranasal sinuses Cerebrospinal fluid rhinorrhea

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potential extended applications. Surgical success is deﬁned as the resolution or the improvement of preoperative symptoms with absence of recurrence for 6 or more months. The absolute indications for surgery for rhinosinusitis are listed in Table 7. Still, there are no real indications for any surgical intervention in uncomplicated cases of acute community-acquired rhinosinusitis [32,33]. The antral sinus tap is the standard of diagnosis of acute maxillary rhinosinusitis, and the adjunctive use of saline irrigation can be of signiﬁcant beneﬁt to reestablish the clearance of sinus secretions from the obstructed sinus cavity. PREVENTION Although it may not be possible to prevent all episodes of acute communityacquired rhinosinusitis, it may be possible to reduce the severity and number of attacks of rhinosinusitis and to prevent the acute form from progressing to a more chronic stage. The following recommendations can be utilized [34]: Adequate hydration to ensure ﬂuidity of nasal secretions Topical intranasal saline mist to moisten nasal mucosa Humidiﬁcation of room air, especially in the winter months Avoidance of chemical irritants such as cigarette smoke or other environmental pollutants Use of a topical decongestant for a few days at the onset of symptoms Oral decongestant therapy to shrink swollen nasal mucosa Avoidance of air travel, or use of topical nasal decongestants to prevent sinus blockage from airplane cabin pressure changes Increased frequency of hand washing to prevent unknown sources of infection and to reduce contamination from respiratory infections Investigation of relationship of upper respiratory allergy in persons with suspicion that seasonal or perennial allergens may precipitate infections. Immunization of patients for viral pathogens with vaccines.

CONCLUSIONS Acute community-acquired rhinosinusitis plays a major role in overall general health concerns. The frequency of these common upper respiratory tract infections have led to the overprescription of antibiotics to assist in the reduction of patient symptoms despite the fact that the majority of these cases begin as common viral illnesses. The diagnosis of acute bacterial rhinosinu-

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sitis should not be made until the symptoms of a viral upper respiratory tract infection last for at least 10 days, or the symptoms worsen after 5 to 7 days. The most common pathogens in this disorder include Streptococcus pneumoniae, Haemophilus inﬂuenza, and Moraxella catarrhalis. The prevalence of antimicrobial resistance, particularly penicillin-resistant S. pneumoniae and b-lactamase–producing organisms, constitutes a major concern in the treatment of these upper respiratory tract infections. Appropriate evaluation of the antimicrobials based on antibiotic susceptibility and eﬃcacy oﬀers the clinician an appropriate choice rather than strict empiric therapy in antimicrobial management of these patients. The guidelines developed by the Sinus and Allergy Health Partnership provided signiﬁcant recommendations for the treatment of ABRS.

REFERENCES 1. Sinus & Allergy Health Partnership. Antimicrobial treatment guidelines for acute bacterial rhinosinusitis. Sinus and Allergy Health Partnership. Otolaryngol Head Neck Surg 2000; 123(1 pt 2):5–31. 2. Gwaltney JM Jr, Jones JG, et al. Medical management of sinusitis: educational goals and management guidelines. The International Conference on Sinus Disease. Ann Otol Rhinol Laryngol Suppl 1995; 167:22–30. 3. Benninger MS, Sedory Holzer SE, et al. Diagnosis and treatment of uncomplicated acute bacterial rhinosinusitis: summary of the Agency for Health Care Policy and Research evidence-based report. Otolaryngol Head Neck Surg 2000; 122(1):1–7. 4. Ray NF, Baraniuk JN, Thamer M, et al. Healthcare expenditures for sinusitis in 1996: contributions of asthma, rhinitis, and other airway disorders. J Allergy Clin Immunol 1996; 103:408–414. 5. McCaig LF, Besser RE, et al. Trends in antimicrobial prescribing rates for children and adolescents. JAMA 2002; 287(23):3096–3102. 6. Poole MD. A focus on acute sinusitis in adults: changes in disease management. Am J Med 1999; 106(5A):38S–47S; discussion 48S–52S. 7. Lanza D, Kennedy D. Adult rhinosinusitis deﬁned. Otolaryngol Head Neck Surg 1997; 117(suppl):S1–S7. 8. Bhattacharyya N. The role of infection in chronic rhinosinusitis. Curr Allergy Asthma Rep 2002; 2(6):500–506. 9. Faststats cdc.gov/nchs/fastats. 10. Gwaltney JM Jr, Acute community-acquired sinusitis. Clin Infect Dis 1996; 23(6):1209–1223; quiz 1224–1225. 11. Gwaltney JM Jr, Scheld WM, et al. The microbial etiology and antimicrobial therapy of adults with acute community-acquired sinusitis: a ﬁfteen-year experience at the University of Virginia and review of other selected studies. J Allergy Clin Immunol 1992; 90(3 pt 2):457–461; discussion 462.

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12. Brook I, Thompson DH, et al. Microbiology and management of chronic maxillary sinusitis. Arch Otolaryngol Head Neck Surg 1994; 120(12):1317–1320. 13. Hartog B, Degener JE, et al. Microbiology of chronic maxillary sinusitis in adults: isolated aerobic and anaerobic bacteria and their susceptibility to twenty antibiotics. Acta Otolaryngol 1995; 115(5):672–677. 14. Brook I, Frazier EH, et al. Microbiology of chronic maxillary sinusitis: comparison between specimens obtained by sinus endoscopy and by surgical drainage. J Med Microbiol 1997; 46(5):430–432. 15. Aust R, Falck B, et al. Studies of the gas exchange and pressure in the maxillary sinuses in normal and infected humans. Rhinology 1979; 17(4):245–251. 16. Cappelletty D. Microbiology of bacterial respiratory infections. Pediatr Infect Dis J 1998; 17(8 suppl):S55–S61. 17. Hadley JA, Schaefer SD. Clinical evaluation of rhinosinusitis: History and physical examination. Otolaryngol Head Neck Surg 1997; 117(3 pt 2):8–11. 18. Report of the Rhinosinusitis Task Force Committee Meeting. Alexandria, Virginia, August 17, 1996. Otolaryngol Head Neck Surg 1997; 117(3 pt 2):S1–S68. 19. Williams JW Jr, Simel DL, Roberts L, Smasa GP. Clinical evaluation for sinusitis: Making the diagnosis by history and physical examination. Ann Intern Med 1992; 117:705–710. 20. Dowell SF, Schwartz B, et al. Appropriate use of antibiotics for URIs in children: Part I. Otitis media and acute sinusitis. The Pediatric URI Consensus Team. Am Fam Physician 1998; 58(5):1113–1118 (1123). 21. Dowell SF, Schwartz B, et al. Appropriate use of antibiotics for URIs in children: part II. Cough, pharyngitis and the common cold. The Pediatric URI Consensus Team. Am Fam Physician 1998; 58(6):1335–1342 (1345). 22. Gold SM, Tami AT. Role of middle meatus aspiration culture in the diagnosis of chronic sinusitis. Laryngoscope 1997; 107(12 pt 1):1586–1589. 23. Talbot GH, Kennedy DW, et al. Rigid nasal endoscopy versus sinus puncture and aspiration for microbiologic documentation of acute bacterial maxillary sinusitis. Clin Infect Dis 2001; 33(10):1668–1675. 24. Zinreich SJ. Rhinosinusitis: radiologic diagnosis. Otolaryngol Head Neck Surg 1997; 117(3 pt 2):S27–S34. 25. Vogan JC, Bolger WE, et al. Endoscopically guided sinonasal cultures: a direct comparison with maxillary sinus aspirate cultures. Otolaryngol Head Neck Surg 2000; 122(3):370–373. 26. AHCPR. Diagnosis and treatment of acute bacterial rhinosinusitis. Rockville, Md: Agency for Healthcare Policy and Research, 1999. 27. Lusk SL. Agency for Health Care Policy and Research guidelines on rhinosinusitis and depression. Aaohn J 1999; 47(12):586–588. 28. Brook I, Yocum P, et al. Bacteriology and beta-lactamase activity in acute and chronic maxillary sinusitis. Arch Otolaryngol Head Neck Surg 1996; 122(4): 418–422; discussion 423. 29. Poole MD, Jacobs MR, et al. Antimicrobial guidelines for the treatment of acute bacterial rhinosinusitis in immunocompetent children. Int J Pediatr Otorhinolaryngol 2002; 63(1):1–13.

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30. Talbot AR, Herr TM, et al. Mucociliary clearance and buﬀered hypertonic saline solution. Laryngoscope 1997; 107(4):500–503. 31. Jones NS. Current concepts in the management of paediatric rhinosinusitis. J Laryngol Otol 1999; 113(1):1–9. 32. Yilmaz G, Varan B, et al. Intranasal budesonide spray as an adjunct to oral antibiotic therapy for acute sinusitis in children. Eur Arch Otorhinolaryngol 2000; 257(5):256–259. 33. Hamilos DL, Thawley SE, Kramper MA, Kamil A, Hamid QA. Eﬀect of intranasal ﬂuticasone on cellular inﬁltration, endothelial adhesion molecule expression and proinﬂammatory cytokine mRNA in nasal polyp disease. J All Clin Immunol 1999; 103:79–87. 34. Damm M, Jungehulsing M, et al. Eﬀects of systemic steroid treatment in chronic polypoid rhinosinusitis evaluated with magnetic resonance imaging. Otolaryngol Head Neck Surg 1999; 120(4):517–523.

10 Otitis Media Scott F. Dowell U.S. Centers for Disease Control and Prevention and Thai Ministry of Public Health Nonthaburi, Thailand

Of all community-acquired respiratory tract infections, otitis media remains the leading indication for antimicrobial therapy among children in the United States. The rate of prescribing declined remarkably during the 1990s, probably a result of broad-based eﬀorts to improve the speciﬁcity of the diagnosis and to limit antimicrobial therapy to those patients who are likely to beneﬁt from it. The recent past has also seen substantial changes in the antimicrobial susceptibility patterns of the leading agents—pneumococcus in particular— and in the perception of the importance of viral agents. Clinicians caring for patients with otitis media now need to carefully consider such options as deferring antimicrobial treatment for many patients, prescribing a shortened course for some, and recommending topical therapy with newer agents for others. Many patients meeting diagnostic criteria for acute otitis media should still be treated with an appropriate course of an antimicrobial agent with eﬃcacy against the major pathogens, although eﬀorts are under way to promote watchful waiting for certain patients. 181

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DIAGNOSIS It may appear self-evident that an accurate diagnosis informs and directs appropriate therapy, but it should be appreciated that the accurate diagnosis of acute otitis media remains one of the most technically demanding skills required of the oﬃce-based clinician [1]. The presence of a perforated tympanic membrane or tympanostomy tubes, with drainage from the middle ear, or of otitis externa, should be conﬁrmed through careful examination, as some of the treatment options diﬀer if these conditions are present. The appearance and mobility of the tympanic membrane is used to identify the presence of a middle ear eﬀusion. In the presence of middle ear eﬀusion, the critical issue is diﬀerentiating acute otitis media (AOM), which may warrant antimicrobial treatment, from otitis media with eﬀusion (OME), which does not [2]. Acute otitis media is diagnosed when the patient has a documented middle ear eﬀusion, accompanied by signs or symptoms of acute inﬂammation [2–4]. Establishing the presence of middle ear eﬀusion is one of the most technically demanding aspects of the ear examination, and requires the consistent use of a properly ﬁtted and maintained pneumatic otoscope, with an attached bulb, a bright light, and an appropriate sized ear speculum [1,3]. Even with the proper equipment, determining if an eﬀusion is present is a challenge. In a comparative study of pediatric residents and otolaryngologists, there was only slight agreement between tympanometry and residents on the presence of eﬀusion (kappa statistic 0.20), and the agreement between tympanometry and otolaryngologists was not much better (kappa 0.32) [5]. The correlation between the two groups on the overall diagnosis of otitis media was fair (kappa 0.30). In the presence of a middle ear eﬀusion, signs and symptoms of acute inﬂammation supporting the diagnosis of AOM include fever, a bulging red or yellow tympanic membrane, or ear pain [2,6,7]. If a middle ear eﬀusion is present but acute inﬂammation is not, the diagnosis is otitis media with eﬀusion (OME), and antimicrobial therapy is not indicated [2]. Antimicrobial therapy for OME has marginal short-term beneﬁt in terms of resolution of the eﬀusion, but there is not evidence that children treated with antibiotics are better oﬀ than those treated with placebo when assessed one or more months after the eﬀusion is noted [8,9].

PATHOGENS Therapy should be directed on the basis of a thorough understanding of the likely pathogens and their predicted susceptibility patterns, as culturedirected therapy is rarely possible or even indicated. The most likely bacterial

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pathogens to cause AOM have changed very little in tympanocentesis studies conducted over the past several decades, which have consistently identiﬁed Streptococcus pneumoniae in about 35% of cases, Haemophilus inﬂuenzae in about 30%, and Moraxella catarrhalis in about 10% (Table 1) [10–13]. Documentation of the role of respiratory viruses, long presumed to be important co-pathogens, has come with the more recent widespread use of nucleic acid ampliﬁcation techniques (Table 1). The role of antimicrobial resistance, which had become a concern with the emergence of h-lactamase producing strains of M. catarrhalis and H. inﬂuenzae in the 1970s, was recognized as increasingly important and resulted in changes in practice with the emergence of multiply resistant strains of S. pneumoniae in the 1990s. Of the major pathogens, the pneumococcus is not only the most commonly identiﬁed, it is also the one most commonly associated with treatment failures, and the least likely to resolve spontaneously if no therapy or inadequate therapy is given. In patients randomized to the placebo or notreatment arm of otitis media treatment trials, approximately 80% of patients infected with M. catarrhalis and 50% of those infected with H. inﬂuenzae have sterile middle ear ﬂuid on reevaluation 3–10 days later, whereas only 20% of similarly untreated patients infected with pneumococci have the infection

TABLE 1

Pathogens Implicated in Acute Otitis Media

Pathogen Bacteria Streptococcus pneumoniae Haemophilus influenzae Moraxella catarrhalis Group A streptococci Other bacteria Viruses Respiratory syncytial virus Influenza virus Rhinoviruses Parainfluenzae viruses Other viruses

Approximate % of patients 25–65 20–40 5–15 1–6 1–8 6–18 3–10 2–24 2–8 3–8

Other bacteria include Chlamydophila pneumoniae, Staphylococcus aureus, atypical mycobacteria, and others. Other viruses include respiratory adenoviruses, coronaviruses, rhinoviruses, enteroviruses, and others. Numbers do not add to 100% because more than one agent may be identiﬁed in a single patient. Source: Refs. 13, 23, 28, 34, 35, and 102.

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resolve without therapy [14,15]. Thus, the pneumococcus is the pathogen of primary concern when selecting an antimicrobial agent, and the presence and antimicrobial susceptibilities of the other pathogens are additional secondary considerations. In the United States, approximately 30% of all invasive pneumococcal isolates are nonsusceptible to penicillin, and most of these nonsusceptible strains also have reduced susceptibility to many of the agents commonly used for the treatment of AOM (Table 2). The mechanism of resistance is important. Pneumococcal resistance to penicillins and cephalosporins is mediated by changes in penicillin-binding proteins, and it can be overcome by moderate increases in the dosage or the use of more active agents [16,17]. Other types of resistance, such as the methylation of ribosomal subunits that results in high-level macrolide resistance, or the double mutations in DNA topoisomerase that results in ﬂuoroquinolone resistance, tend to confer absolute resistance to the drug or class of drugs involved [16,18,19]. Haemophilus inﬂuenzae has maintained a steady second position to pneumococcus as an important pathogen in acute otitis media, and antimicrobial agents used to treat AOM should be selected with this pathogen in mind. The dramatic decreases in invasive H. inﬂuenzae type b disease that

TABLE 2 Antimicrobial Susceptibility of Streptococcus pneumoniae to Agents Commonly Used to Treat Acute Otitis Media Streptococcus pneumoniae susceptibility according to penicillin-susceptibility category Agent Amoxicillin Cefprozil Cefpodoxime Cefuroxime Cefaclor Cefixime Ceftibuten Ceftriaxone (injection) Macrolidesa Trimethoprim-sulfamethoxazole

Susceptible (75%)

Intermediate (10%)

Resistant (16%)

+++ +++ +++ +++ +++ +++ +++ +++ +++ ++

+++ ++ ++ + +++ +

+ ++

Note. Estimated percentage of pneumococci covered by agent is as follows: +++, at least 90%; ++, >75%; +, >50%; <50%. a ‘‘Macrolides’’ refers to erythromycin, clarithromycin, and azithromycin. Source: Refs. 13, 17, 59, 103, and 104.

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followed widespread use of the conjugate vaccine did little to decrease Haemophilus in otitis media, because most middle ear ﬂuid isolates are nontypeable. During the 1970s and 1980s, the proportion of H. inﬂuenzae that produce h-lactamase increased to approximately one-third of all strains, but this proportion did not change appreciably during the 1990s [20,21]. Moraxella catarrhalis is consistently identiﬁed in a minority of middle ear ﬂuid specimens from patients with AOM. The proportion of strains producing h-lactamase is now greater than 90% in most studies [20,22]. In spite of this, treatment with agents to which M. catarrhalis is not susceptible (such as amoxicillin) rarely results in treatment failures from persisting M. catarrhalis [12,23,24]. Presumably this is because of the high rate of spontaneous resolution of AOM associated with M. catarrhalis [14]. Other bacteria are occasionally isolated from middle ear ﬂuid of patients with AOM, including group A streptococci, Staphylococcus aureus, and gram-negative rods. Recently, Chlamydophila pneumoniae has been detected in approximately 10% of middle ear aspirates by polymerase chain reaction [25] or by culture [26]. If these ﬁndings are conﬁrmed in other studies, it may be necessary to consider eﬃcacy against C. pneumoniae in future antimicrobial treatment guidelines. The fact that respiratory viruses can be detected in middle ear ﬂuid and play a role in the pathogenesis of acute otitis media has been appreciated for several decades [27–29], but the more recent ﬁnding that inﬂuenza vaccines may substantially reduce the incidence of acute otitis media has led to renewed interest in the role of viruses and the opportunities for prevention [30–33]. Children often present with AOM during or after an upper respiratory infection, and it is easy to demonstrate the presence of respiratory viruses in the nasopharynx and occasionally the middle ear ﬂuid of such children [34,35]. The most commonly identiﬁed viruses are respiratory syncytial virus, inﬂuenza virus, human rhinoviruses, and parainﬂuenza viruses [34,35], but enteroviruses, adenoviruses, coronaviruses, herpex simplex virus, cytomegalovirus, human herpesvirus-6, and others have occasionally been identiﬁed as well [35–37]. Experimental studies with human volunteers and observational studies on children with colds have documented that viral infection of the middle ear cavity can lead to negative pressure and eustachian tube dysfunction, presumed to be an initiating event in facilitating entry of bacterial pathogens from the nasopharynx to the middle ear space [38,39]. Often, both viruses and bacterial pathogens are detected in the middle ear ﬂuid at the same time, and there is evidence to suggest that such co-infection is associated with an increased risk of treatment failure [28,40]. It is not clear that viruses alone are an important cause of AOM. Whether viruses act as cofactors, initiating and exacerbating bacterial AOM, or whether they act alone, it seems clear that controlling viral in-

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fections is likely to substantially reduce the incidence of AOM. Early ﬁndings that immunization of children with injected subunit inﬂuenza vaccines was associated with reductions in AOM of 30% to 36% [30,31] have been conﬁrmed and extended by studies of the newer, live attenuated intranasal inﬂuenza vaccines [32,33]. Vaccines against other respiratory viruses are in various stages of testing, and it seems likely that vaccines against respiratory syncytial virus in particular, but perhaps also those against the parainﬂuenza viruses or others, will contribute substantially to the control of AOM in the future. TREATMENT First-Line Antimicrobial Therapy There is no doubt that antimicrobial therapy beneﬁts patients with documented AOM. It also is true that most episodes of AOM will resolve with or without therapy. Traditional estimates of the beneﬁt of treatment are modest—on the order of 15% (80% of AOM episodes treated with placebo will resolve by 14 days, compared with 95% treated with an appropriate agent) [41,42]. Some now argue that even these modest estimates of eﬃcacy are too high, that the true beneﬁt is even smaller, and that this small beneﬁt does not outweigh the potential adverse eﬀects of unnecessary treatment, such as carriage or invasive disease caused by resistant organisms [43–45]. However, the newer estimates of eﬃcacy are still in the same range as traditional estimates (i.e., 13% [45] and 12% [44]), and there is clear evidence in these trials of measurable clinical beneﬁt in terms of shortened duration of fever and reduced pain. In nonsevere cases in a randomized trial, more than 90% of episodes were signiﬁcantly improved by 48 hr, whether treated with amoxicillin or placebo. Initial treatment failure (persistent fever of z38jC or severe pain after 48 hr) occurred in 3.9% of amoxicillin-treated patients and 7.7% of those treated with placebo ( P = 0.009) [46]. Finally, there is now some evidence that the rates of mastoiditis may be higher in the Netherlands and other countries where antimicrobial therapy is not routinely prescribed [47]. In view of the documented beneﬁt from antimicrobial treatment for a minority of patients, in terms of accelerated eradication of the pathogen, shortening of the duration of ear pain and fever, and potentially in terms of reduction in the likelihood of mastoiditis or other complications, it seems reasonable to prescribe an antimicrobial agent to certain patients appropriately diagnosed with AOM, and the question becomes, ‘‘which children?’’ and ‘‘which antibiotic?’’ The reduction in pneumococcal disease observed with the use of the new conjugate pneumococcal vaccine may also inﬂuence the risk/beneﬁt consid-

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erations involved in weighing the decision to treat children with AOM. Reductions in AOM on the order of 6–8% have been seen in the controlled trials of the vaccine [48]. Although the magnitude of reduction is small, there is also evidence that widespread use of the vaccine may result in reductions in multiply resistant pneumococci and in serotype replacement by nonvaccine serotypes. Young children with documented AOM should be treated. The American Academy of Pediatrics is considering adopting watchful waiting as an option for certain low-risk older children. These might include those who are 2 years of age or older, are otherwise healthy, have no history of recurrent AOM, no craniofacial abnormalities, no evidence of immune compromise, and have only mild to moderate symptoms. The primary consideration in selecting an antimicrobial agent is eﬃcacy against the major pathogens. Secondary considerations are cost, palatability, convenience of dosing schedules, and eﬀects on antimicrobial resistance. Eﬃcacy is best measured by microbiological outcomes in studies that include tympanocentesis to identify the organism and repeat tympanocentesis for patients who have treatment failures documented on days 3 through 5. Such studies have now established that early eradication of pathogens from middle ear ﬂuid is associated with improved clinical outcome [49]. On the other hand, comparison of eﬃcacy using less precisely deﬁned measures of outcome often lead to the false conclusion that the two agents being compared have equivalent eﬃcacy, an observation aptly dubbed the ‘‘Pollyanna phenomenon’’ after the blind optimism of the heroine of the novel by that name [50]. Antimicrobial eﬃcacy correlates with clinical eﬃcacy. Patients infected with penicillin-nonsusceptible pneumococci were more likely to have documented bacteriological failure of treatment with cefuroxime, and even more likely to fail treatment with cefaclor, a cephalosporin with relatively low activity against nonsusceptible pneumococci [17]. In this study and others like it, bacteriologic failure was consistently correlated with clinical failure [17,49,51]. Amoxicillin remains the ﬁrst-line agent for treating uncomplicated acute otitis media, despite the many changes in antimicrobial susceptibility of the leading bacterial pathogens. Of the available oral agents, amoxicillin has among the highest antibacterial eﬃcacy for S. pneumoniae, the major pathogen of concern, especially when given at the high dosages currently recommended (80–90 mg/kg/day) [52–55]. Amoxicillin also has good antimicrobial and clinical eﬃcacy against two-thirds of H. inﬂuenzae and occasional M. catarrhalis, but this latter pathogen is very likely to resolve on its own even without treatment. Amoxicillin is also inexpensive and well tolerated, and it enjoys a strong safety record as the leading agent for otitis media treatment over more than 3 decades of use [55].

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Second-line Agents Second-line agents should be considered for patients who return with persisting symptoms during amoxicillin treatment, for those with documented penicillin allergy, and for those known to be at increased risk for infection with resistant strains. Treatment outcome should be assessed in children who are not improved by day 3, not at the traditional 10-day ear recheck. Patients who return with persistent and unimproved signs and symptoms at day 3 are likely to have microbiological treatment failure, and should have antimicrobial treatment optimized at that time [41]. A 10-day recheck is likely to be too late to inﬂuence the duration of pain or fever with a change in therapy, because these symptoms resolve in most patients within the ﬁrst week, even among patients treated with placebo. Furthermore, more than 70% of patients will have a persistent eﬀusion at 10–14 days, despite successful treatment of the AOM episode and eradication of the pathogen [56,57]. One might anticipate that patients who return after failing therapy with amoxicillin would be more likely to be infected with h-lactamase–producing strains of H. inﬂuenzae or M. catarrhalis, because those strains would not be eradicated by amoxicillin, whereas the drug is highly active against pneumococci. However, even in cases where amoxicillin treatment has failed, pneumococci remain predominant pathogens, with h-lactamase–producing strains of H. inﬂuenzae or M. catarrhalis present to a lesser extent [23]. Presumably this is related to the increased likelihood of spontaneous resolution of H. inﬂuenzae or M. catarrhalis compared with pneumococci, but it has implications for the selection of agents for children with treatment failure. Such agents must be active against pneumococci, including penicillin-nonsusceptible strains, as well as having h-lactamase stability. In 1999 the Centers for Disease Control and Prevention (CDC) recommended three agents with appropriate antimicrobial coverage and documented clinical eﬃcacy for patients who fail amoxicillin therapy: amoxicillin-clavulanate, cefuroxime axetil, and intramuscular ceftriaxone (Table 3) [41]. Each of these agents has good activity against intermediate-penicillinsusceptible pneumococci and is stable against h-lactamase–producing strains of H. inﬂuenzae and M. catarrhalis. However, amoxicillin-clavulanate is expensive, cefuroxime axetil has a bitter taste, and cefriaxone requires an injection. In the years since these recommendations were made, additional information on these and other agents and on the likely pathogens in cases of treatment failure has become available, and has reinforced the importance of treating with agents eﬀective against nonsusceptible pneumococci and hlactamase–producing H. inﬂuenzae [23,48,58]. Recent anecdotal reports of treatment failure with cefuroxime and surveillance information about its

Day 0

Amoxicillinb; amoxicillin/ clavulanateb; cefuroxime axetil

Yes

Amoxicillin/clavulanateb; cefuroxime axetil; I.M. ceftriaxonec I.M. ceftriaxonec; clindamycind; or tympanocentesis-guided therapy

Amoxicillin/clavulanateb; cefuroxime axetil; I.M. ceftriaxonec Amoxicillin/clavulanate; cefuroxime axetil; I.M. ceftriaxonec, or tympanocentesis-guided therapy

Treatment failurea on days 10–28

Note. Strong evidence for efficacy of these agents was available in 1999. Other drugs that may also be effective are discussed in the text. a Treatment failure is defined as a lack of clinical improvement in signs and symptoms such as ear pain, fever, and tympanic membrane findings of redness, bulging, or otorrhea. Persisting middle ear effusion is expected in up to 70% of appropriately treated patients at 10–28 days and should not be considered as evidence of treatment failure. b Amoxicillin and amoxicillin/clavulanate should generally be given at 80 to 90 mg/kg/day. The clavulanate component should be given at 6.4 mg/kg/day (requires newer formulations or combination with amoxicillin). c Intramuscular ceftriaxone in one to three daily injections of 50 mg/kg. d Clindamycin is not effective against Haemophilus influenzae or Moraxella catarrhalis. Source: Ref. 55.

Amoxicillin

No

b

Treatment failurea on day 3

Treatment Recommendations for Acute Otitis Media

Antibiotics in prior month

TABLE 3

Otitis Media 189

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possibly decreased eﬃcacy against penicillin nonsusceptible pneumococci have led some authorities to question its inclusion as a second-line agent [59– 61]. Ceftriaxone can be given as either 1-day injection or a 3-day course, and some evidence now exists that the single dose is comparable clinically to 10 days of amoxicillin-clavulanate [62]. However, in direct comparison using bacteriological eﬃcacy as an outcome measure, the 3-day course is superior [51]. High-dose amoxicillin-clavulanate does appear to be bacteriologically and clinically eﬃcacious against penicillin-nonsusceptible pneumococci and H. inﬂuenzae [53], although it has a substantial eﬀect on subsequent nasopharyngeal colonization with resistant organisms [63]. In addition to the three agents listed above, newer information indicates that other agents may meet these criteria. Cefdinir, for example, is active against h-lactamase–producing strains of H. inﬂuenzae or M. catarrhalis and has the advantage of palatability and convenient dosing, although some evidence indicates the eﬃcacy against intermediate susceptible pneumococci may not be as good as amoxicillin-clavulanate or ceftriaxone [64–66]. Cefprozil and cefpodoxime have reasonable in vitro activity against intermediate pneumococci [41]. A recent comparison of cefprozil with amoxicillin clavulanate reported similar clinical eﬃcacy, although the more sensitive microbiological eﬃcacy outcome was not assessed [67]. Second-line agents may also be considered for patients who present with an increased likelihood of infection with resistant pathogens. Such patients include those who present with AOM within one month of completing a course of an antibiotic, those with well-documented previous treatment failures, and those on long-term antimicrobial prophylaxis. For patients with a history of a serious allergic reaction to penicillin, other classes of agent must be considered. In this context, the macrolides and related agents (azithromycin, clarithromycin, and erythromycin) would be appropriate alternatives. For those children who have a history of rash or other nonspeciﬁc symptoms following treatment with amoxicillin, it may be more appropriate to select one of the cephalosporins with better eﬃcacy against nonsusceptible pneumococci, as cross-reactivity between the penicillins and cephalosporins is approximately 15% [68]. In cases where there is tympanic membrane perforation or a tympanostomy tube in place, topical treatment with ﬂuoroquinolone or other otic drops may also be an appropriate approach [69]. Less Useful Agents Some agents that may have been useful in the past may no longer be appropriate for treatment of AOM. Trimethoprim-sulfamethoxazole was considered a ﬁrst-line agent for many years [70,71], but increasing resistance and recent evidence of bacteriologic and clinical failure make this agent a poor

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choice for most areas where resistant pneumococci are a concern. In U.S. and international pneumococcal surveillance studies, resistance to trimethoprimsulfamethoxazole ranges from 30% to more than 60% [13,59,72]. A study using repeat tympanocentesis documented bacteriological failure in 73% of those infected with a trimethoprim-sulfamethoxazole–resistant pneumococcus, and these bacteriological failures correlated directly with clinical failure [72]. Erythromycin and related agents have similarly been useful drugs for AOM treatment in the past, but the utility of these agents is also threatened by increasing antimicrobial resistance. Macrolide resistance among pneumococci has increased rapidly in recent years, doubling from 10% to 20% in association with a 320% increase in prescribing to young children in one U.S. national study [73]. Much of the resistance observed is due to the less concerning eﬄux mechanism, rather than the higher-level resistance associated with ribosomal methylation, but the degree of resistance associated with eﬄux has also increased, with increasing minimal inhibitory concentrations (MICs) even among those isolates with eﬄux mediated resistance [59,73]. Repeat tympanocentesis studies have documented a strong correlation between high azithromycin MICs among pneumococci and bacteriological and clinical treatment failure for AOM [54,74] and worrisome failures to eradicate H. inﬂuenzae as well [54]. In regions where macrolide resistance is less of a concern and in patients with penicillin allergy, the macrolide agents are likely to remain attractive options, especially because of the convenient dosing and palatability of the newer agents. Several of the oral cephalosporins approved for treatment of AOM are also suboptimal choices in the era of increasing pneumococcal resistance because of their poor activity against nonsusceptible pneumococci. These agents include cefaclor, ceﬁxime, loracarbef, and ceftibuten (Table 2) [17,41,74]. Adjunctive treatment of AOM with antihistamines and decongestants has often been prescribed despite mixed evidence for eﬃcacy. Most carefully conducted controlled trials have found no beneﬁt, some have documented worrisome side eﬀects. A recent systematic review found no evidence for eﬃcacy of either antihistamines or decongestants, and marginal beneﬁts only in some less rigorous trials of combination therapy [75]. In view of the documented and signiﬁcant increase in side eﬀects [75], these agents should have little or no future role in AOM treatment.

OTHER TREATMENT OPTIONS Deferring Antibiotic Therapy Some authorities now argue that deferring antimicrobial therapy for children with AOM is the preferred option [43], and that parents and physicians are

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willing to forgo antibiotic treatment of AOM because of concerns about antimicrobial resistance [76]. As discussed above, the evidence that 12% to 15% of children will beneﬁt with decreased duration of pain and fever, prompt eradication of the pathogen, and possibly lower risk of complications argues that antimicrobial treatment of AOM remains appropriate for many children. Older children with mild AOM and no history of recurrent AOM, craniofacial abnormalities, or immune compromise may be managed with watchful waiting for 2–3 days as long as follow-up is assured. As well, children with OME should be clearly diﬀerentiated, and deferral of antimicrobial therapy for this condition is the appropriate option [2,58]. Several controlled community trials have demonstrated that antimicrobial use for respiratory tract infections can be reduced by 10% to 30% in a single year with education directed at physicians and patients [77–80]. These decreases are encouraging and come in addition to the substantial annual declines of 8% to 10% in prescribing seen in the control groups in all of these trials. The declines in prescribing in the control groups reﬂect a wider trend in the United States and elsewhere to use antimicrobial agents more judiciously, as advocated by many [81–84]. These eﬀorts have paid dividends in terms of reduced prescribing. For otitis media, prescribing on a population basis throughout the United States decreased by a remarkable 47% between 1990 and 2000 [85]. Short-Course Therapy One way of reducing excessive antimicrobial use is to shorten the prescribed course from the traditional 10 days, and this approach has the added beneﬁt of simplifying treatment for parents and potentially increasing compliance. A number of randomized trials have compared outcomes with shortened courses and reported favorable comparison to traditional regimens [86–91]. Recommendations from the CDC and American Academy of Pediatrics in 1998 endorsed shortened courses for children 2 years or older with mild and uncomplicated AOM [2] and a meta-analysis published in that year lent support to the recommendations [92]. Since that time, concerns about antimicrobial resistance and resulting treatment failures have increased. Additional information from large trials has reenforced earlier ﬁndings that full 10-day courses of treatment are measurably superior to shorter courses, although the diﬀerences are most pronounced in the younger children and those more prone to treatment failure [93–95]. On the other hand, the proposed beneﬁt of shortened courses of therapy on reduced carriage of resistant strains has been substantiated [96]. Treatment of selected children with 5- to 7-day courses of antimicrobial agents remains an appropriate option, but children younger than 2 years of

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age, those with perforated tympanic membranes, craniofacial abnormalities or other underlying conditions predisposing to otitis media, and those with chronic or recurrent otitis media should not be considered candidates for shortened courses of therapy. These considerations apply to shortened courses of therapy with traditional 10-day oral h-lactam regimens, not to the previously discussed 3-day regimen of intramuscular ceftriaxone or 5-day courses of azithromycin, both of which have prolonged half-lives and may therefore provide antimicrobial eﬀects well beyond the last administered dose. Topical Therapy For patients with otitis externa, topical therapy with otic drops containing aminoglycosides or other antimicrobial agents, often in combination with corticosteroids and mechanical removal of ﬂuid and cerumen, has been the traditional treatment of choice. With the availability of newer ﬂuoroquinolone topical preparations, attention has turned to a broadened set of indications for topical therapy with these agents, including patients with chronic suppurative otitis media, AOM with tympanic membrane perforation, and AOM with tympanostomy tubes in place, in addition to those with otitis externa [69,97]. Controlled trials comparing topical ﬂuoroquinolone treatment with traditional therapy are limited, but it appears that topical therapy with ciproﬂoxacin or oﬂoxacin oﬀers comparable or slightly improved bacteriological eﬃcacy to traditional topical preparations for otitis externa or chronic suppurative otitis media [98–100]. In addition, topical oﬂoxacin appears to oﬀer comparable cure rates and a broadened spectrum of coverage compared to oral amoxicillin-clavulanate for patients with AOM who have tympanostomy tubes in place [69,101]. More direct comparisons of topical with oral therapy are warranted before topical therapy can be recommended as a preferred option. In the meantime, clinicians caring for patients with tympanostomy tubes and/or drainage in the ear canal in the era of increasing antimicrobial resistance may welcome the additional treatment option provided by the newer topical agents. CONCLUSIONS National campaigns to reduce unnecessary antibiotic use have been highly successful; nevertheless, otitis media remains a leading indication for antimicrobial use. Eﬀorts to further reduce unnecessary antimicrobial use continue, including the anticipated promotion of watchful waiting for low-risk children with acute otitis media. Observation with analgesia and careful follow-up is an option for selected older children. All antimicrobial agents are

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not equally eﬃcacious. If tympanocentesis is used to document bacteriological eradication, some agents can be shown to be clearly superior, and others ineﬀective. High-dose amoxicillin remains the ﬁrst-line drug of choice, and several other h-lactam agents are reasonable second-line options. Deferral of antimicrobial therapy for patients without clear evidence of AOM, shortcourse therapy for low-risk patients, and topical treatment for those with nonintact tympanic membranes are viable options that should be considered. REFERENCES Block S. Accurately diagnosing acute otitis media: ‘‘dispose of the disposables.’’ Pediatr Infect Dis J 1998; 17:1179–1180. 2. Dowell SF, Marcy SM, Phillips WR, Gerber MA, Schwartz B. Otitis media— principles of judicious use of antimicrobial agents. Pediatrics 1998; 101:165– 171. 3. Faden H, Duﬀy L, Boeve M. Otitis media: back to basics. Pediatr Infect Dis J 1998; 17:1105–1112; quiz 1112–3. 4. Isaacson G. The natural history of a treated episode of acute otitis media. Pediatrics 1996; 98:968–971. 5. Steinbach WJ, Sectish TC, Benjamin DK Jr, Chang KW, Messner AH. Pediatric residents’ clinical diagnostic accuracy of otitis media. Pediatrics 2002; 109:993–998. 6. Schwartz RH, Rodriguez WJ, Brook I, Grundfast KM. The febrile response in acute otitis media. JAMA 1981; 245:2057–2058. 7. McCormick DP, Lim-Melia E, Saeed K, Baldwin CD, Chonmaitree T. Otitis media: can clinical ﬁndings predict bacterial or viral etiology? Pediatr Infect Dis J 2000; 19:256–258. 8. Williams RL, Chalmers TC, Stange KC, Chalmers FT, Bowlin SJ. Use of antibiotics in preventing recurrent acute otitis media and in treating otitis media with eﬀusion. A meta-analytic attempt to resolve the brouhaha. JAMA 1993; 270:1344–1351. 9. Rosenfeld RM, Post JC. Meta-analysis of antibiotics for the treatment of otitis media with eﬀusion. Otolaryngol Head Neck Surg 1992; 106:378–386. 10. Mortimer E, Watterson R. A bacteriologic investigation of otitis media in infancy. Pediatrics 1956; 17:359–366. 11. Jacobs MR. Increasing importance of antibiotic-resistant Streptococcus pneumoniae in acute otitis media. Pediatr Infect Dis J 1996; 15:940–943. 12. Harrison CJ, Marks MI, Welch DF. Microbiology of recently treated acute otitis media compared with previously untreated acute otitis media. Pediatr Infect Dis J 1985; 4:641–646. 13. Jacobs MR, Dagan R, Appelbaum PC, Burch DJ. Prevalence of antimicrobial-resistant pathogens in middle ear ﬂuid: multinational study of 917 children with acute otitis media. Antimicrob Agents Chemother 1998; 42: 589–595. 1.

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Heikkinen T, Ruuskanen O, Waris M, Ziegler T, Arola M, Halonen P. Inﬂuenza vaccination in the prevention of acute otitis media in children. Am J Dis Child 1991; 145:445–448. Clements DA, Langdon L, Bland C, Walter E. Inﬂuenza A vaccine decreases the incidence of otitis media in 6- to 30-month-old children in day care. Arch Pediatr Adolesc Med 1995; 149:1113–1117. Belshe RB, Gruber WC. Safety, eﬃcacy and eﬀectiveness of cold-adapted, live, attenuated, trivalent, intranasal inﬂuenza vaccine in adults and children. Philos Trans R Soc Lond B Biol Sci 2001; 356:1947–1951. Marchisio P, Cavagna R, Maspes B, et al. Eﬃcacy of intranasal virosomal inﬂuenza vaccine in the prevention of recurrent acute otitis media in children. Clin Infect Dis 2002; 35:168–174. Pitkaranta A, Virolainen A, Jero J, Arruda E, Hayden FG. Detection of rhinovirus, respiratory syncytial virus, and coronavirus infections in acute otitis media by reverse transcriptase polymerase chain reaction. Pediatrics 1998; 102:291–295. Heikkinen T, Thint M, Chonmaitree T. Prevalence of various respiratory viruses in the middle ear during acute otitis media. N Engl J Med 1999; 340: 260–264. Barone SR, Kaplan MH, Krilov LR. Human herpesvirus-6 infection in children with ﬁrst febrile seizures. J Pediatr 1995; 127:95–97. Chonmaitree T, Owen MJ, Patel JA, Hedgpeth D, Horlick D, Howie VM. Presence of cytomegalovirus and herpes simplex virus in middle ear ﬂuids from children with acute otitis media. Clin Infect Dis 1992; 15:650–653. Buchman CA, Doyle WJ, Skoner D, Fireman P, Gwaltney JM. Otologic manifestations of experimental rhinovirus infection. Laryngoscope 1994; 104: 1295–1299. Winther B, Hayden FG, Arruda E, Dutkowski R, Ward P, Hendley JO. Viral respiratory infection in schoolchildren: eﬀects on middle ear pressure. Pediatrics 2002; 109:826–832. Sung BS, Chonmaitree T, Broemeling LD, et al. Association of rhinovirus infection with poor bacteriologic outcome of bacterial-viral otitis media. Clin Infect Dis 1993; 17:38–42. Dowell SF, Butler JC, Giebink GS. Acute otitis media: management and surveillance in an era of pneumococcal resistance. Drug-Resistant Streptococcus Pneumoniae Therapeutic Working Group. Nurse Pract 1999; 24:1–9; quiz 15-6. Rosenfeld RM, Vertrees JE, Carr J, et al. Clinical eﬃcacy of antimicrobial drugs for acute otitis media: metaanalysis of 5400 children from thirty-three randomized trials. J Pediatr 1994; 124:355–367. Culpepper L, Froom J. Routine antimicrobial treatment of acute otitis media: is it necessary? JAMA 1997; 278:1643–1645. Takata GS, Chan LS, Shekelle P, Morton SC, Mason W, Marcy SM. Evidence assessment of management of acute otitis media: I. The role of antibiotics in treatment of uncomplicated acute otitis media. Pediatrics 2001; 108:239–247.

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Damoiseaux RA, van Balen FA, Hoes AW, Verheij TJ, de Melker RA. Primary care based randomised, double blind trial of amoxicillin versus placebo for acute otitis media in children aged under 2 years. BMJ 2000; 320:350–354. Kaleida PH, Casselbrant ML, Rockette HE, et al. Amoxicillin or myringotomy or both for acute otitis media: results of a randomized clinical trial. Pediatrics 1991; 87:466–474. Van Zuijlen DA, Schilder AG, Van Balen FA, Hoes AW. National diﬀerences in incidence of acute mastoiditis: relationship to prescribing patterns of antibiotics for acute otitis media? Pediatr Infect Dis J 2001; 20:140–144. Klein JO. Management of otitis media: 2000 and beyond. Pediatr Infect Dis J 2000; 19:383–387. Dagan R, Leibovitz E, Greenberg D, Yagupsky P, Fliss DM, Leiberman A. Early eradication of pathogens from middle ear ﬂuid during antibiotic treatment of acute otitis media is associated with improved clinical outcome. Pediatri Infect Dis J 1998; 17:776–782. Marchant CD, Carlin SA, Johnson CE, Shurin PA. Measuring the comparative eﬃcacy of antibacterial agents for acute otitis media: the ‘‘Pollyanna phenomenon.’’ J Pediatr 1992; 120:72–77. Leibovitz E, Piglansky L, Raiz S, Press J, Leiberman A, Dagan R. Bacteriologic and clinical eﬃcacy of one day vs. three day intramuscular ceftriaxone for treatment of nonresponsive acute otitis media in children. Pediatr Infect Dis J 2000; 19:1040–1045. Pelton SI. Acute otitis media in an era of increasing antimicrobial resistance and universal administration of pneumococcal conjugate vaccine. Pediatr Infect Dis J 2002; 21:599–604; discussion 613-4. Dagan R, Hoberman A, Johnson C, et al. Bacteriologic and clinical eﬃcacy of high dose amoxicillin/clavulanate in children with acute otitis media. Pediatr Infect Dis J 2001; 20:829–837. Dagan R, Johnson CE, McLinn S, et al. Bacteriologic and clinical eﬃcacy of amoxicillin/clavulanate vs. azithromycin in acute otitis media. Pediatr Infect Dis J 2000; 19:95–104. Dowell SF, Butler JC, Giebink GS, et al. Acute otitis media: management and surveillance in an era of pneumococcal resistance—a report from the Drugresistant Streptococcus pneumoniae Therapeutic Working Group. Pediatr Infect Dis J 1999; 18:1–9. Klein JO. Otitis media. Clin Infect Dis 1994; 19:823–833. Teele DW, Klein JO, Rosner BA. Epidemiology of otitis media in children. Annals of Otology, Rhinology, & Laryngology - Supplement 1980; 89:5–6. Klein JO. Review of consensus reports on management of acute otitis media. Pediatr Infect Dis J 1999; 18:1152–1155. Whitney CG, Farley MM, Hadler J, et al. Increasing prevalence of multidrugresistant Streptococcus pneumoniae in the United States. N Engl J Med 2000; 343:1917–1924. Dowell SF, Smith T, Leversedge K, Snitzer J. Failure of treatment of

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Dowell pneumonia associated with highly resistant pneumococci in a child. Clin Infect Dis 1999; 29: 462–463. Hoberman A, Marchant CD, Kaplan SL, Feldman S. Treatment of acute otitis media consensus recommendations. Clin Pediatr (Phila) 2002; 41:373–390. Cohen R, Navel M, Grunberg J, et al. One dose ceftriaxone vs. ten days of amoxicillin/clavulanate therapy for acute otitis media: clinical eﬃcacy and change in nasopharyngeal ﬂora. Pediatr Infect Dis J 1999; 18:403–409. Ghaﬀar F, Muniz LS, Katz K, et al. Eﬀects of large dosages of amoxicillin/ clavulanate or azithromycin on nasopharyngeal carriage of Streptococcus pneumoniae, Haemophilus inﬂuenzae, nonpneumococcal alpha-hemolytic streptococci, and Staphylococcus aureus in children with acute otitis media. Clin Infect Dis 2002; 34:1301–1309. Block SL, McCarty JM, Hedrick JA, Nemeth MA, Keyserling CH, Tack KJ. Comparative safety and eﬃcacy of cefdinir vs amoxicillin/clavulanate for treatment of suppurative acute otitis media in children. Pediatr Infect Dis J 2000; 19:S159–S165. Adler M, McDonald PJ, Trostmann U, Keyserling C, Tack K. Cefdinir versus amoxicillin/clavulanate acid in the treatment of suppurative acute otitis media in children. Eur J Clin Microbiol Infect Dis 1997; 16:214–219. Adler M, McDonald PJ, Trostmann U, Keyserling C, Tack K. Cefdinir vs. amoxicillin/clavulanic acid in the treatment of suppurative acute otitis media in children. Pediatr Infect Dis J 2000; 19:S166–S170. Hedrick JA, Sher LD, Schwartz RH, Pierce P. Cefprozil versus high-dose amoxicillin/clavulanate in children with acute otitis media. Clin Ther 2001; 23: 193–204. Dowell S. Treatment of otitis media. Pediatr Infect Dis J 2000; 19:1032–1033. Klein JO. In vitro and in vivo antimicrobial activity of topical oﬂoxacin and other ototopical agents. Pediatr Infect Dis J 2001; 20:102–103; discussion 120-2. Cameron GG, Pomahac AC, Johnston MT. Comparative eﬃcacy of ampicillin and trimethoprim-sulfamethoxazole in otitis media. Can Med Assoc J 1975; 112:87–88. Barnett ED, Teele DW, Klein JO, Cabral HJ, Kharasch SJ. Comparison of ceftriaxone and trimethoprim-sulfamethoxazole for acute otitis media. Greater Boston Otitis Media Study Group. Pediatrics 1997; 99:23–28. Leiberman A, Leibovitz E, Piglansky L, et al. Bacteriologic and clinical eﬃcacy of trimethoprim-sulfamethoxazole for treatment of acute otitis media. Pediatr Infect Dis J 2001; 20:260–264. Hyde TB, Gay K, Stephens DS, et al. Macrolide resistance among invasive Streptococcus pneumoniae isolates. JAMA 2001; 286:1857–1862. Dagan R, Leibovitz E, Fliss DM, et al. Bacteriologic eﬃcacies of oral azithromycin and oral cefaclor in treatment of acute otitis media in infants and young children. Antimicrob Agents Chemother 2000; 44:43–50. Flynn CA, Griﬃn G, Tudiver F. Decongestants and antihistamines for acute otitis media in children. Cochrane Database Syst Rev 2002; CD001727.

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Sorum PC, Shim J, Chasseigne G, et al. Do parents and physicians diﬀer in making decisions about acute otitis media? J Fam Pract 2002; 51:51–57. Finkelstein JA, Davis RL, Dowell SF, et al. Reducing antibiotic use in children: a randomized trial in 12 practices. Pediatrics 2001; 108:1–7. Hennessy TW, Petersen KM, Bruden D, et al. Changes in antibiotic-prescribing practices and carriage of penicillin-resistant Streptococcus pneumoniae: a controlled intervention trial in rural Alaska. Clin Infect Dis 2002; 34:1543– 1550. Perz JF, Craig AS, Coﬀey CS, et al. Changes in antibiotic prescribing for children after a community-wide campaign. JAMA 2002; 287:3103–3109. Belongia EA, Sullivan BJ, Chyou PH, Madagame E, Reed KD, Schwartz B. A community intervention trial to promote judicious antibiotic use and reduce penicillin-resistant Streptococcus pneumoniae carriage in children. Pediatrics 2001; 108:575–583. Paradise JL. Managing otitis media: a time for change. Pediatrics 1995; 96:712– 715. Dowell SF, Marcy SM, Phillips WR, Gerber MA, Schwartz B. Principles of judicious use of antimicrobial agents for pediatric upper respiratory tract infections. Pediatrics 1998; 101:163–165. McCracken GH. Treatment of acute otitis media in an era of increasing microbial resistance. Pediatr Infect Dis J 1998; 17:576–579. Schwartz B, Bell DM, Hughes JM. Preventing the emergence of antimicrobial resistance: A call for action by clinicians, public health oﬃcials, and patients. JAMA 1997; 278:944–945. McCaig L, Besser R, Hughes J. Decline in pediatric antimicrobial drug prescribing among oﬃce-based physicians in the United States, 1989–1998. Abstracts of the 2000 IDSA Conference. New Orleans, LA: Infectious Disease Society of America, 2000. Chaput de Saintonge DM, Levine DF, Savage IT, et al. Trial of three-day and ten-day courses of amoxycillin in otitis media. BMJ 1982; 284:1078–1081. Meistrup-Larsen KI, Sorensen H, Johnsen NJ, Thomsen J, Mygind N, Sederberg-Olsen J. Two versus seven days penicillin treatment for acute otitis media. A placebo controlled trial in children. Acta Otolaryngol (Stockh) 1983; 96:99–104. Bain J, Murphy E, Ross F. Acute otitis media: clinical course among children who received a short course of high dose antibiotic. BMJ 1985; 291:1243–1246. Jones R, Bain J. Three-day and seven-day treatment in acute otitis media: a double-blind antibiotic trial. Journal of the Royal College of General Practitioners 1986; 36:356–358. Hendrickse WA, Kusmiesz H, Shelton S, Nelson JD. Five vs. ten days of therapy for acute otitis media. Pediatr Infect Dis J 1988; 7:14–23. Gooch WMR, Blair E, Puopolo A, et al. Eﬀectiveness of ﬁve days of therapy with cefuroxime axetil suspension for treatment of acute otitis media. Pediatric Infect Dis J 1996; 15:157–164. Kozyrskyi AL, Hildes-Ripstein GE, Longstaﬀe SEA, et al. Treatment of acute

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11 Acute Pharyngitis James S. Tan Northeastern Ohio Universities College of Medicine, Rootstown and Summa Health System Akron, Ohio, U.S.A.

Blaise L. Congeni Northeastern Ohio Universities College of Medicine, Rootstown and Children’s Hospital Medical Center of Akron Akron, Ohio, U.S.A.

Acute pharyngitis is among the most frequent illnesses seen in the primary care practice. It is characterized by the presence of increased redness and an exudate or ulceration in the pharynx or tonsil or a membrane that covers the tonsils [1]. Most cases of acute pharyngitis are viral and require only symptomatic treatment. This chapter will emphasize pharyngitis caused by group A beta hemolytic streptococcus (GABHS) because it is the most common bacterial etiology that can be treated with antibiotic therapy and it is associated with suppurative and nonsuppurative complications. ETIOLOGY AND EPIDEMIOLOGY Bacterial and viral agents known to be common etiologic agents of pharyngitis are listed in Table 1. GABHS is the most common bacterial agent 201

Microbial Causes of Acute Pharyngitis

Source: Ref. 2.

Viral Rhinovirus (100 types and 1 subtype) Coronavirus (3 or more types) Adenovirus (types 3, 4, 7, 14, and 21) Herpes simplex virus (types 1 and 2) Parainfluenza virus (type 1–4) Influenzavirus (types A and B) Coxsackievirus A (types 2, 4–6, 8, and 10) Epstein-Barr virus Cytomegalovirus Human immunodeficiency virus type 1 Bacterial Streptococcus pyogenes (group A h-hemolytic streptococci) Group C and G h-hemolytic streptococci Mixed anaerobes Neisseria gonorhoeae Corynebacterium diphtheriae Arcanobacterium haemolyticum Yersinia enterocolitica Yersina pestis Franciscella tularensis Chlamydia Chlamydia pneumoniae Chlamydia psittaci Mycoplasma Mycoplasma pneumoniae

Pathogens

TABLE 1

Pneumonia, bronchitis, and pharyngitis

Pneumonia, bronchitis, and pharyngitis Acute respiratory disease and pneumonia

Pharyngitis and tonsillitis; scarlatiniform rash Vincent’s angina Pharyngitis Diphtheria Pharyngitis, scarlatiniform rash Enterocolitis Plague Oropharyngeal form of tularemia

Pharyngitis and tonsillitis, scarlet fever

Common cold Common cold Pharyngoconjunctival fever, acute respiratory disease Gingivitis, stomatitis, pharyngitis Common cold, croup Influenza Herpangina Infectious mononucleosis Infectious mononucleosis Primary human immunodeficiency virus infection

Syndrome or disease

<1

Unknown <1

5 <1 <1 <1 <1 <1 <1 <1

15–30

20 >5 5 4 2 2 <1 <1 <1 <1

Estimated percentage of cases

202 Tan and Congeni

Acute Pharyngitis

203

causing acute pharyngitis. It accounts for approximately 15–30% of cases in children and 5–10% in adults [2]. Much less common causes of acute pharyngitis are group C and group G streptococci. Both of these groups have been associated with isolated infections, endemic pharyngitis, and community outbreaks, especially among adults [3]. GABHS may occur as outbreaks or endemic infections and is most commonly found in children. Outbreaks are frequently associated with crowding in close quarters. Endemic spread is commonly through contact transmission. PATHOGENESIS The extracellular products and toxins produced by GABHS exert damage to the host. These products include streptolysin S and O, streptokinase, DNAase, protease, and pyrogenic exotoxins (erythrogenic toxin responsible for scarlet fever). M protein and M protein–like substances are part of the component of the bacterial cell wall. They contribute to the bacterial virulence by making the bacteria less recognizable by the immune system. There are more than 100 antigen-distinct types of M proteins. One of their functions is to resist destruction by the phagocytes. This resistance can be blocked by M protein–speciﬁc antibody. CLINICAL MANIFESTATIONS Pharyngitis is an infection that is ubiquitous: it attacks most people at least once a year. Most cases of viral pharyngitis are associated with an upper respiratory tract infection (nasopharyngitis). Nasopharyngitis has a prodrome that may include malaise, diaphoresis, fever, headache, and general aches and pains. Coryza and sore throat follow. Many infections will progress to produce a cough and/or laryngitis. Some viral infections produce predominantly coryza, others more pharyngitis, and others more cough or laryngitis. In streptococcal pharyngitis, the clinical signs are not unique and are diﬃcult to distinguish from those caused by other infections. The classic manifestations of pharyngitis—signiﬁcant pharyngeal edema with or without exudates, strawberry tongue, tender cervical lymph nodes, abdominal pain, and rash—are frequently absent. In addition, the clinical ﬁndings diﬀer among age groups; hence, young children, school-age children, and adults may have various presentations. Snow et al., in their position paper on the appropriate use of antibiotics in acute pharyngitis, stated that the most reliable predictors of streptococcal pharyngitis include tonsillar exudates, tender anterior cervical lymphadenopathy, history of fever, and absence of cough [4]. They recommended using the Centor criteria [5] in deciding whether to treat

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empirically without conﬁrmation by culture or rapid antigen testing [4,6]. The sensitivity of the Centor criteria has not been determined. Bisno and Kaplan disagreed with the above recommendations of empiricism by Snow et al. and suggested that 60% of the patients would have no GABHS in the throat culture [7]. Steinhoﬀ et al., in their study of Egyptian children between ages 2 and 13 years of age, showed that symptoms of exudative pharyngitis, tender lymph nodes, and observed temperature greater than 38.0jC each had a high speciﬁcity but low sensitivity [8]. Using a positive culture for GABHS as the conﬁrmatory test, the sensitivity was only 12.1% when the combined presence of all of the following criteria were used [9]—namely, fever, pharyngeal exudates, tender enlarged palpable cervical lymph node, and pain on swallowing; however, the speciﬁcity was 93.9%. Based on the above ﬁndings, it appears that there is not enough information to support empiric treatment based on clinical criteria alone. It should be emphasized that hoarseness, coughing, runny eyes, or coryza is rarely associated with group A streptococci in any age group [10]. Diﬀerentiating clinical features found in viral sore throats are as follows: the presence of fever, sore throat and ulcers in the posterior pharynx is suggestive of Coxsackievirus infection; measles should be considered when the patient has pharyngitis, conjunctivitis, rash, and Koplik spots; parainﬂuenza and inﬂuenza viruses are often associated with a particularly painful pharyngitis accompanied by cough and hoarseness; viral mononucleosis syndrome may also produce pharyngitis with or without exudates— hence, HIV, EBV, herpes simplex, and CMV can produce signiﬁcant pharyngitis and tend to last longer than other viral causes of pharyngitis, but lymph nodes are generally only mildly tender or not tender at all; in herpes infection, gingivostomatitis may also be observed; rhinovirus, RSV, and coronavirus may present with pharyngitis symptoms but cervical lymphadenopathy and exudative pharyngitis are not found. Streptococci belonging to Lanceﬁeld groups B, C, and G have been reported to cause pharyngitis as well [2,3,11–13]. Generally, the symptoms are milder. Recurrent or chronic pharyngitis is not uncommon. Approximately 10–25% of patients with GABHS pharyngitis treated with penicillin have bacteriologic failures [14,15]. About half of the patients with GABHS in the pharynx are carriers and do not have active disease and may be misclassiﬁed as failures. These streptococcal carriers have no detectable clinical symptoms and no serologic response. Treatment is not necessary, because the carrier state presents no risk for rheumatic fever. Other bacterial agents have been associated with acute pharyngitis: Haemophilus inﬂuenzae may cause pharyngitis and epiglottitis; Corynebacterium diphtheriae is associated with pharyngitis with membrane formation,

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also known as diphtheria; Arcanobacterium haemolyticum, formerly known as Corynebacterium haemolyticum, is also known to cause pharyngitis [16,17]. Some patients may present with scarlet fever–like skin rash. Neisseria gonorrhoeae [18] and Yersinia enterocolitica have also been associated with acute pharyngitis symptoms [19]. Chlamydia pneumoniae and Mycoplasma pneumoniae can cause pharyngitis, but generally will go on to cause cough also, often with wheezing and pneumonia [14,20]. Mixed anaerobic bacterial infections due to spirochetes and fusobacterium (Vincent’s angina) cause occasional cases of acute pharyngitis [20]. LABORATORY DIAGNOSIS Throat culture for the presence of group A streptococci in the throat continues to be the gold standard; however, it does not diﬀerentiate infection from the carrier state. False negatives may result from previous antibiotic administration or poor sampling technique such as failure to properly swab the posterior pharynx, tonsils, and tonsillar fossae. Rapid antigen testing using enzyme immunoassay (EIA) in the oﬃce provides timely diagnostic information within minutes and has been recommended by various investigators [21,22]. Most of these tests have a reported sensitivity between 60% and 90% and high speciﬁcity to indicate the presence of group A streptococcus infection [23]. The sensitivity of the rapid antigen test is proportional to the number of positive clinical criteria devised by Centor [24]. However, this test does not provide the bacteria for susceptibility testing, and similar to the culture, this rapid antigen test may be positive in carriers. In their cost-eﬀective analysis of management of sore throats in children, Tsevat and Kotagal concluded that throat culture is the least costly strategy [25]. Serologic tests such as antistreptolysin O (ASO) and anti-deoxyribonuclease (anti-DNase B), although useful in conﬁrming the presence of recent infection, are not useful in the acute management of sore throat. For suspected viral causes of pharyngitis, serologic tests for antibody response to EBV and CMV, or rapid antigen tests for adenovirus, RSV, and parainﬂuenza may be ordered. MANAGEMENT Viruses are the most common cause of pharyngitis in the majority of patients. These individuals do not require antimicrobial therapy. GABHS is the most common cause of bacterial pharyngitis. Antimicrobial therapy should be limited to patients with a high probability of GABHS infection. The clinical signs and symptoms are not speciﬁc. The desired outcomes in the treatment of

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pharyngitis due to GABHS are to prevent nonsuppurative complications such as rheumatic fever and post-streptococcal glomerulonephritis, and to prevent suppurative complications (peritonsillar abscess, cervical lymphadenitis, and mastoiditis), to reduce clinical symptoms and discomfort, to allow the rapid resumption of usual activities, to reduce transmission to close contacts, and ﬁnally, to minimize the potential adverse eﬀects from the use of inappropriate antimicrobial agents [14]. ANTIMICROBIAL THERAPY Penicillin, given intramuscularly or orally, remains the drug of choice for streptococcal pharyngitis. Other agents such as macrolides (especially azithromycin) and cephalosporins have been shown to have at least equal efﬁcacy in eradication of the streptococci in the pharynx, and more convenient dosing. Since 1953, the American Heart Association has recommended, for oral treatment, a regimen of penicillin 3 to 4 times a day for 10 days to maximize eradication of bacteria [26]. Initial attempts to shorten the duration using penicillin V were not successful because of lower rates of microbiologic eradication [27–30]. The Dutch national guidelines appeared to have reached a compromise and advocated the treatment of streptococcal pharyngitis for 7 days [31,32]. The latest guideline from the IDSA and the Red Book continue to recommend a 10-day course of oral penicillin as ﬁrstline treatment [14,33]. Because compliance is a problem when penicillin is given 3 to 4 times a day, once-daily and twice-daily dosing have been investigated [34,35]. Oncedaily dosing of penicillin was not eﬀective, but twice-daily dosing of penicillin was found to be as eﬀective as 3 to 4 doses a day [36]. In addition, once-daily oral amoxicillin appears to be just as eﬀective [36]. The twice-daily regimen using penicillin V is presently recommended in the IDSA guideline and the Red Book [14,33]. Cephalosporins have an equal if not better eﬃcacy compared with oral penicillin. Cefdinir, ceﬁxime, cefpodoxime, ceftibuten, and cefuroxime have been shown to be eﬀective [37–41]. For example, Pichichero reported a bacteriologic eradication rate of 90% for a 5-day course of cefpodoxime and 78% for a 10-day course of penicillin V [41]. However, a 10-day course of cefpodoxime had an even better eradication rate of 95%. Erythromycin is traditionally recommended for a 10-day course. The new macrolides—namely, azithromycin and clarithromycin—have been shown to have equal eradication rate of GABHS with a 5-day course [42,43]. The apparent superiority of cephalosporins and azithromycin in microbiologic eradication compared to penicillins in studies may reﬂect their

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greater activity against the carrier state and not necessarily improved clinical activity [44]. However, at present the use of the shorter course has not been endorsed by IDSA or the Red Book [14,33]. GABHS has not been reported to have resistance to h-lactam agents; however, resistance to macrolides has been reported worldwide [45–52]. There are two major mechanisms of macrolide resistance, namely, target modiﬁcation, and active eﬄux [53]. Interference of the binding of the macrolide to its target on the ribosomal RNA of the bacteria is caused by a ribosomal methylase encoded by an ermAM gene. This enzyme causes ribosomal conformation changes resulting in inducible or constitutive crossresistance to macrolide, and lincomyin and streptogramin B (MLSB phenotype) resistance. This modiﬁcation results in high-level macrolide resistance (MIC z 64 Ag/mL). Active eﬄux is another mechanism of resistance. It is macrolide speciﬁc and is encoded by mef gene (M phenotype). Resistance to one macrolide—for example, erythromycin—means resistance to the other macrolides such as azithromycin, clarithromycin, and roxithromycin in either M or MLSB phenotype. Strains of streptococcus with low-level resistance (MIC = 1–32 Ag/mL) are commonly associated with the presence of mefE gene. These bacterial cells have an active pump that causes the macrolide to be moved from intracellular to extracellular sites. These bacteria are usually susceptible to clindamycin. Strains of streptococcus that have a high level of macrolide resistance are usually resistant to clindamycin. This resistance is commonly mediated by the erm gene. Although the outcome of macrolide treatment in those infected with macrolide-resistant streptococcal pharyngitis is uncertain, it is prudent not to treat these patients with macrolides. With increasing incidence of macrolide resistance worldwide, including the United States, the use of empiric macrolide treatment of pharyngitis should be reconsidered when the incidence of community macrolide resistance is high. Because of the increasing number of publications recommending not to do throat cultures and sensitivity but to rely on clinical presentation or rapid streptococcal scre en [4,54], it will become more diﬃcult for a community to know the true incidence of local antimicrobial resistance pattern including macrolide resistance. By adding a keto group to C3 of the macrolide molecule, a new group of compounds, ketolides, with better antibacterial activities and less susceptibility to MLSB resistance has emerged [55]. The ﬁrst member of this group that has been submitted for Food and Drug Administration approval is telithromycin. This antimicrobial agent has a very similar spectrum of activity as the new macrolides, including coverage of streptococci. For penicillin-allergic patients, macrolides or clindamycin may be used if the local resistance pattern is known. Pending FDA approval, a ketolide may also be considered. The use of trimethoprim/sulfamethoxazole

Antimicrobial agent, dosage

First-line treatment recommendation for treatment of acute pharyngitis and prevention of acute rheumatic fever Oral Penicillin V Children: 250 mg b.i.d. or t.i.d. Adolescents and adults: 250 mg t.i.d. or q.i.d. Adolescents and adults: 500 mg b.i.d. Oral Amoxicillin Adolescents and adults: 750 mg once daily Oral First-generation cephalosporins Cephalexin and cephradine Children: 25–50 mg/kg/d in 2 divided doses Adolescents and adults: 500 mg b.i.d. Cefadroxil Children: 30 mg/kg once daily Adolescents and adults: 1 g once daily IM Benzathine penicillin G 1.2 million units Benzathine penicillin G 600,000 units (children <27 kg) Mixtures of benzathine and procaine penicillin (dose should be based on benzathine penicillin)

Route

A-II A-II C-III A-II See belowb

A-II A-II B-II

10 days 10 days

1 dose 1 dose 1 dose

Ratinga

10 days 10 days 10 days

Duration

Antimicrobial Therapy for Group A Streptococcal Pharyngitis (Recommendation based mainly on the Practice Guideline from the Infectious Diseases Society [14])

TABLE 2

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5 days

days days days days days

A-II

10 days

5 5 5 5 5

A-II

10 days

Rating based on strength of evidence: A = Good evidence to support a recommendation for use; B = Moderate evidence to support a recommendation for use; C = Poor evidence to support a recommendation; D = Moderate evidence to support a recommendation against use; E = Good evidence to support a recommendation against use. Rating based on quality of evidence: I = Evidence from z1 properly randomized controlled trial; II = Evidence from >1 well-designed clinical trial, without randomization; from cohort or case-controlled analytic studies (preferably from >1 center); from multiple time-series; or from dramatic results of uncontrolled experiments. b Not rated by IDSA, however, it stated that amoxicillin has equal efficacy [36]. c Based on WHO recommendation [10]. d Based on Bisno [2].

a

For patients allergic to penicillin Oral Erythromycin (dose varies with formulation) Erythromycin ethylsuccinate 40 mg/kg/day (maximum 1.5/day) t.i.d.c Erythromycin estolate 20–240 mg/kg/day (maximum 1.5 g/day) t.i.d.c Erythromycin stearate 1 g per day in 2 or 4 divided dosesd Oral First-generation cephalosporins (should not be used to treat patients with immediate-type hypersensitivity to h-lactam antibiotics) The following shorter course recommendations are not endorsed by IDSA, WHO, and the Redbook [26,54,60] Oral Cefadroxil Oral Cefixime Oral Cefdinir Oral Cefpodoxime Oral Azithromycin 500 mg first day followed by 250 mg daily for 4 more days Oral Clarithromycin 500 mg daily

Acute Pharyngitis 209

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and tetracycline is not recommended because of the high percentage of resistance. Most failure in eradicating streptococci with penicillin may be due to (1) antibiotic noncompliance, (2) reinfection, (3) local bacteria interference, (4) penicillin tolerance, (5) presence of h-lactamase–producing oral microﬂora, or (6) existence of carrier state [1]. Brook et al. observed that following penicillin therapy, children harbor h-lactamase–producing bacteria in the oropharynx. The h-lactamase produced by these organisms may protect GABHS from the action of penicillin and other h-lactams [56]. Therefore, agents that are not susceptible to h-lactamase action, such as clindamycin or amoxicillin/ clavulanate, may be more eﬀective [15,57]. Similarly, in patients with multiple episodes of pharyngitis occurring over months or years, a 10-day course of therapy with clindamycin 20–30 mg/ day in three divided doses (in children) or 600 mg/day in two to four divided doses; or amoxicillin/clavulanate 40 mg/kg/day in three divided dose or 500 mg in two divided doses may be advisable because this combination has been shown to yield high rates of eradication of streptococci from the pharynx. For parenteral therapy, single dose of 1.2 million unites of benzathine intramuscularly with or without rifampin 20 mg/kg/day or 300 mg twice daily for 4 days [14]. ANCILLARY MANAGEMENT AND PREVENTION For a patient with a single episode of streptococcal pharyngitis, a further work-up of the patient or the family is not recommended after antimicrobial therapy unless there is concern about proven recurrent GABHS pharyngitis; routine repeat throat swabs for cultures of the patients or asymptomatic members of the family is not recommended. There is no credible evidence to suggest that the family pet may be the source of GABHS [58]. Children with GABHS pharyngitis should complete a full 24 hours of antibiotic therapy before returning to school or day-care [59]. The IDSA guidelines detailed six indicators of quality of care [14]: (1) obtain microbiologic testing (i.e., throat cultures or rapid antigen detection assay) in patients suspected of having GABHS; (2) patients with positive acute pharyngitis plus a positive test for GABHS should be treated with one of the antimicrobial regimens recommended (see Table 2); (3) antimicrobial therapy should be withheld or discontinued in patients with negative microbiological test results for GABHS; (4) microbiologic testing is not needed in asymptomatic patients who have received an adequate course of antimicrobial therapy; (5) microbiologic testing is not necessary for asymptomatic family contacts of patients of GABHS infection; and (6) avoid prescribing

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continuous long-term antimicrobial prophylaxis to prevent recurrent episodes of acute pharyngitis except in patients with acute rheumatic fever.

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12 Acute Exacerbations of Chronic Obstructive Pulmonary Disease Antonio Anzueto and Sandra G. Adams The University of Texas Health Science Center at San Antonio and The South Texas Veterans Health Care System San Antonio, Texas, U.S.A.

INTRODUCTION The diagnosis and treatment of acute exacerbations of chronic obstructive pulmonary disease (AECOPD) is controversial. In this chapter, we will review (1) the epidemiology of this condition; (2) the etiology—many patients with AECOPD are thought to have a combination of viral and bacterial infections, which contribute to their exacerbation; bacterial organisms are isolated more commonly after viral infections in patients with chronic obstructive pulmonary disease (COPD), and the role that bacterial infections play in AECOPD remains a very controversial topic; (3) the use of diagnostic procedures; (4) the eﬃcacy of antibiotics; (5) clinical parameters used to stratify patients’ severity; (6) the diﬀerent groups of antibiotics that can be used; and (7) other therapies, including bronchodilators. We will summarize the current literature with special emphasis on the safety and eﬃcacy of the commonly prescribed drugs. 215

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EPIDEMIOLOGY Chronic obstructive pulmonary disease (COPD) comprises several clinical conditions, including chronic bronchitis, emphysema, and asthma, that often coexist. Patients are prone to exacerbations under conditions that are usually associated with increased breathlessness; often, there is increase in cough, which may be productive of mucoid or purulent sputum and malaise. These symptoms may produce signiﬁcant decrement in quality of life. Acute exacerbation of chronic bronchitis (AECOPD) is the classic term that is used in the literature to describe a heterogeneous group of patients, and it involves a wide variety of management recommendations. The interpretation of data in the literature is confusing and diﬃcult to generalize due to the many diﬀerences in these populations. The term AECOPD is used throughout this section to describe the typical patient who is over the age of 40 years and has obstructive lung disease by PFTs [1]. Although many of these patients also have chronic bronchitis (as previously deﬁned clinically as presence of persistent productive cough for more than three consecutive months in two consecutive years) [2], they are not required to have a chronic, productive cough to be included in this current deﬁnition of AECOPD. Acute exacerbations are the common cause of morbidity and mortality in this patient population [3,4]. Figure 1A shows the prevalence by age of chronic bronchitis and Figure 1B shows the prevalence by age of emphysema in the United States. COPD currently accounts for approximately 110,00 deaths per year, making it—after heart disease, cancer, and stroke—the fourth leading cause of death (Fig. 1C). It has been estimated that by the year 2020, it will be the third cause of death [5–7]. The cost of treating acute exacerbation COPD is very high, not only because of the economic impact but also because of the increase in morbidity and early mortality. COPD in the United States annually accounts for 16,000,367 oﬃce visits, 500,000 hospitalizations, and $18 billion in direct health care cost [5,6,8]. Despite treatment with antibiotics, bronchodilators, and corticosteroids, up to 28% of patients discharged from the emergency department with acute exacerbations have recurrent symptoms within 14 days [9], and 17% relapse and require hospitalization [10]. Signiﬁcant numbers of hospitalized patients with acute exacerbations have modiﬁable risk factors, including inﬂuenza vaccination, oxygen supplementations, smoking, and occupational exposures. The ability to identify patients who are at risk for relapse should improve decisions about hospital admissions and follow-up appointments. Several investigators have conﬁrmed that relapse is more likely among patients who have lower pretreatment or posttreatment FEV1, those who receive more bronchodilator treatments or corticosteroids during visits, and those who have higher rates of previous relapse. These factors can provide clinical guidance on the basis of

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FIGURE 1 (A) Prevalence of chronic bronchitis by age in the United States from 1970 to 1996; (B) prevalence of emphysema by age in the United States from 1970 to 1996; (C) and death due to COPD 1998. (From Refs. 3 and 5.)

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FIGURE 1 Continued.

identifying predictors of failure, but it has a very poor sensitivity and speciﬁcity. For example, the deﬁnition ‘‘return to the emergency department of less than 14 days after initial presentation’’ has a sensitivity of 57% and a speciﬁcity of 72% [11]. Several studies have tried to identify the risk factors associated with mortality with acute exacerbation. The Study to Understand Prognosis and Preferences for Outcomes and Rates of Treatment (SUPPORT) enrolled 1016 patients who had severe acute exacerbation of COPD at hospital admission [12] due to respiratory infections, including pneumonia (48%), congestive heart failure (26%), worsening respiratory failure due to lung cancer (3.3%), pulmonary emboli (1.4%), and pneumothorax (1%). The 180-day mortality rate was 33% and the 2-year mortality rate was 49%. Signiﬁcant predictors of mortality include acute physiology and chronic health evaluation (APACHE III) score [13], body mass index, age, functional status 2 weeks prior to admission, lower ratio of PO2 to FIO2, congestive heart failure, serum albumen level, cor pulmonale, lower activities of daily living scores, and lower scores on the Duke Activity Status Index. This study also reported that only 25% of patients were both alive and able to report a good, very good, or excellent quality of life 6 months after discharge. In another large prospective cohort study of patients who were admitted to intensive care units with COPD-related respiratory failure [14], the inhospital mortality rate, 23.8%, was predicted by number of hospital days before transfer to intensive care unit, and the non/respiratory component of

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the APACHE III score. A separate analysis to identify true predictors of 180day mortality included acute physiological score, age, and hospital days before transfer to intensive care unit. A separate analysis to identify true predictors of 180-day mortality included acute physiological score, old age, and more hospital days before transfer to intensive care unit. Activities of daily living were also signiﬁcant predictors of univariate analysis [14]. In a recent report, a cohort of 101 patients with moderate to severe COPD (mean FEV1 41.9% predicted), which was closely followed up for 2.5 years, increased dyspnea and colds at onset of exacerbation were associated with prolonged recovery times. Recovery was incomplete in a signiﬁcant proportion of COPD exacerbations [15]. Patients with frequent exacerbations (median 3 to 8/year) experience signiﬁcantly worse quality of life, as measured by the St George’s Respiratory Questionnaire. Factors that predict frequent exacerbations were the number of exacerbations in the previous year and a history of bronchitic symptoms (cough and sputum production), though lung function was not related [16]. ETIOLOGY Although respiratory infections are assumed to be the main risk factors for exacerbation of COPD, other factors are also involved [17]. Health education of patients, smoking cessation, pulmonary rehabilitation, good nutritional status, and early medical intervention are all considered helpful in preventing exacerbations [18,19]. Table 1 summarizes other known risk factors for exacerbation of COPD. During bacterial infection in AECOPD, a variety of microorganisms have been shown to be associated with these exacerbations, including Haemophilus inﬂuenzae, Haemophilus parainﬂuenzae, Moraxella catarrhalis, and Streptococcus pneumoniae [20]. It has been described that a minority of these patients have atypical pathogens such as Mycoplasma pneumoniae and Chlamydia pneumoniae, but because of limitations with the diagnosis, the true prevalence of these organisms is not known (Fig. 2). There have been several recent studies demonstrating that patients with the most severe obstructive lung disease have a signiﬁcantly higher prevalence of gram-negative organisms such as Enterobacteriaceae and Pseudomonas species [21–23]. One of the ﬁrst groups of investigators to report these ﬁndings was Eller et al. [21], who evaluated sputum cultures from 112 inpatients with AECOPD. Sixty-four percent of patients with an FEV1 of 35% of less predicted versus only 30% of those with FEV1 of 50% or more ( P = 0.016) had evidence of gram-negative organisms. The most commonly isolated organisms (from these patients with severe obstructive lung disease) included Enterobacteriaceae and Pseudomonas species, Proteus vulgaris,

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TABLE 1

Anzueto and Adams Differences in Characteristics Based on Antibiotic Selection First-line

Days of therapy 8.9 F 3.3 Weeks between AECOPD 17.1 F 22 14-day failure rate (N = 36) 19% Hospitalizations (% of total failures) 53% Cost per episode (US $) 942 F 2173

Second-line

Third-line

8.3 F 2.3 22.7 F 30 16% 14% 563 F 2296

7.5 F 2.5a 34.3 F 35.5a 7%a 8%a 542 F 1946

Data are presented in percentages (as indicated) and otherwise in mean F standard deviation. a P V 0.05 third-line versus first-line. Source: Ref. 48.

Serratia marcescens, Stenotrophomonas maltophilia, and Escherichia coli. Miravitlles et al. [22] recently published a study with similar results that also supported these ﬁndings. These investigators evaluated the relationship between FEV1 and the isolation of diverse pathogens in the sputum of 91 patients with COPD who presented with type 1 (severe) or type 2 (moderate) symptoms of AECOPD. Patients were separated into groups by FEV1 (z50% versus <50% predicted). There were signiﬁcantly larger numbers of H. inﬂuenzae and P. aeruginosa in the group with FEV1 less than 50% predicted ( P<0.05). In contrast, there were signiﬁcantly larger numbers of non– potentially pathogenic microorganisms in the group with FEV1 of 50% or more ( P<0.05). These authors also performed a multivariate analysis with logistic regression and found that H. inﬂuenzae was cultured signiﬁcantly

FIGURE 2 Most frequent microorganisms isolated in acute exacerbation of COPD.

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more commonly in patients who were actively smoking (odds ratio [OR] 8.2, conﬁdence interval [CI] 1.9–43) and whose FEV1 was less than 50% predicted (OR 6.85, CI 1.6–52). P. aeruginosa was also cultured signiﬁcantly more frequently in those with poor lung function, FEV1 less than 50% (OR 6.6, CI 1.2–124) (Fig. 3). Pathogenesis Although the role of smoking in COPD is well established, tobacco smoking is not the sole factor responsible. Airway infection has been suggested as an important cause for the worsening of this disease. COPD is an inﬂammatory disease and exacerbations are associated with an additional increase in airway inﬂammation (measured in sputum), especially in exacerbations associated with bacterial infection [24]. Murphy and Sethi [25] proposed the vicious cycle hypothesis (Fig. 4). This hypothesis proposes that airway damage from chronic infection or colonization occurs in these patients when the bacteria cause the host to continuously release inﬂammatory mediators. Persistent infection results in lung inﬂammation and, as a consequence, lung function progressively decreases. The host response to infection is inﬂammatory cells that are found in sputum both in stable COPD and during acute exacerbations. These cells are primarily neutrophils and macrophages. Inﬂammatory mediators that are of signiﬁcance in attracting these inﬂammatory cells to the airway are interleukin-6 (IL-6), interleukin-8 (IL-8), tumor necrosis factor– a (TNF-a ) and leukotrine B4 (LTB4). End products of these inﬂammatory cells that mediate airway damage are neutrophil elastase (NE) and matrix

FIGURE 3 The relation of pathogens isolated in patients with COPD and the severity of lung function (FeV1). (From Ref. 22.)

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FIGURE 4 Vicious cycle hypothesis—relationship of lung injury and persistent infection. (From Ref. 25.)

metalloproteinases (MMPs). Sputum inﬂammatory markers increase substantially with during AECOPD and therefore could represent useful objective indicators of response to treatment [26]. Recent observations have shown that the inﬂammation in COPD extends beyond the lung, and increased inﬂammatory markers are measurable in the serum, and further increase with exacerbations [27,28]. Patients with recurrent AECOPD suﬀer with signiﬁcant morbidity associated with their condition. Kanner et al. [29] evaluated the loss of lung function of 5887 smokers with obstruction to airﬂow by PFTs (FEV1/ FVC <70%, with FEV1 of 55%–90%) in the Lung Health Study. These investigators grouped all of the self-reported illnesses that occurred in this population together as lower respiratory infections (LRI), which included episodes of bronchitis, pneumonia, inﬂuenza, and chest colds. Several important ﬁndings were reported in this study: (1) continuous smokers had signiﬁcantly more LRI than sustained quitters ( P = 0.0003), which was due to an increased number of LRI with time in continuous smokers, but not in sustained quitters, (2) continuous smokers with chronic bronchitis had LRI rates that were 158–189% of those without chronic bronchitis ( P < 0.001), (3) LRI rates increased with time in continuous smokers whether or not they reported chronic bronchitis ( P = 0.008), and (4) in continuous smokers

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with 1.5 LRI or more per year, over 44% of the mean predicted loss in lung function (measured by FEV1) per year was attributed to these acute exacerbations. Therefore, evaluation of the participants of this study with mild COPD demonstrated that self-reported LRI were associated with signiﬁcant long-term adverse eﬀects on lung function in those who continued to smoke cigarettes. This study provides further evidence supporting the ‘‘vicious cycle hypothesis.’’ Diagnostic Procedures A recent evidence-base analysis has summarized the best available information related to the use of diagnostic tests in AECOPD [30,31]. These reviews concluded that data on the utility of most diagnostic tests are limited. However, chest radiography and arterial blood gas sampling seem useful, whereas acute spirometry does not. On the basis of observational studies of patients with AECOPD treated in emergency departments or hospitals, chest radiographs are a useful diagnostic test. One study evaluated 685 patients: chest radiographs showed a 16% abnormality rate, mainly the presence of inﬁltrates consistent with pneumonia [32]. In another prospective cohort study of 128 hospital admissions for asthma or COPD, 21% of patients had a change in management that was prompted by the chest radiograph. Most patients had new pulmonary inﬁltrate or evidence of congestive heart failure [33]. We recommend that in patients with AECOPD, if they are evaluated in an emergency room and/or require hospitalization, a chest radiograph be obtained in order to rule out any other abnormalities. Although the CT scan is more sensitive, and therefore potentially valuable in evaluation of the acute exacerbation, there are no randomized, controlled trials on which to base a recommendation. Spirometric assessment at presentation or during treatment of acute exacerbation is not useful in judging the severity or guiding the management of the patient. Peak expiratory ﬂow rate and FEV1 are correlated (r = 0.84; P < 0.001), but the FEV1 showed no signiﬁcant correlation with PO2 and only weak correlation with PCO2 [10]. At this time, there are no data to support the routine use of peak ﬂow meters or FEV1 assessment as useful in the management of COPD exacerbations; therefore, we do not recommend it.

TREATMENT WITH ANTIBIOTICS The speciﬁc etiology of AECOPD is diﬃcult to determine in an outpatient oﬃce setting on the basis of symptoms and signs. Sputum studies, although they can be potentially useful, have signiﬁcant limitations in routine use mainly related to the delay in obtaining the results, cost, and lack of sensitivity

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and speciﬁcity. Recent treatment guidelines for AECOPD reﬂect the lack of evidence-base data to provide speciﬁc recommendations for the use of antibiotics [30,31]. The GOLD guideline, which was a NHLBI/WHO initiative for COPD recommend antibiotic choices on the basis of local sensitivity patterns of the most common pathogens associated with AECOPD, but did not provide any speciﬁc guidelines [1]. There have been a number of clinical trials examining the use of antibiotics in the treatment of AECOPD [17–20]. Many of the earlier studies showed either no beneﬁt, or minimal beneﬁt, when antibiotics were prescribed. Some of the more recent publications, including a recent meta-analysis [34], demonstrated a beneﬁt of antibiotics during an acute exacerbation, but not in preventing exacerbations. In 1987, Anthonisen et al. [35] reported the results of a large-scale placebo-controlled trial designed to determine the eﬀectiveness of antibiotics in the treatment of AECOPD. In this study, 173 patients with chronic bronchitis were followed for 3.5 years, during which time they had 362 exacerbations. This study ﬁnally brought some conformity to the deﬁnition of AECOPD and was the ﬁrst widely accepted classiﬁcation for the severity of presenting symptoms. Patients who are classiﬁed in the severe range of ‘‘AECOPD’’ include those with all three clinical symptoms (of increased shortness of breath, increased sputum production, and a change in sputum purulence) at initial presentation. The patients were randomized to either antibiotics or placebo in a double-blind, crossover fashion. Three oral antibiotics were used (chosen by the primary physician) for 10 days: amoxicillin, trimethoprim-sulfamethoxazole (co-trimoxazole), and doxycycline. Approximately 40% of all exacerbations were type 1 (severe), 40% were type 2 (moderate), and only 20% were type 3 (mild). Patients with the most severe exacerbations (type 1) received a signiﬁcant beneﬁt from antibiotics, whereas there was no signiﬁcant diﬀerence between antibiotic and placebo in patients who had only one of the deﬁned symptoms (type 3). Overall, the antibiotictreated patients showed a more rapid improvement in peak ﬂow, a greater percentage of clinical successes, and a smaller percentage of clinical failures than those who received placebo. In addition, the length of illness was 2 days shorter for the antibiotic-treated group. The major criticisms of this study were that no microbiology test was performed and that all antibiotics were assumed to be equivalent. Allegra et al. [36] found signiﬁcant beneﬁt with the use of amoxicillinclavulanate acid (AugmentinR) therapy compared with placebo in patients with severe disease. Patients who received this antibiotic exhibited a higher success rate (86.4% vs. 50.3% in the placebo group, P < 0.01) and a lower frequency of recurrent exacerbations. In 1995, Saint et al. [34] published the results of a meta-analysis examining the role of antibiotics in the treatment of AECOPD (Fig. 5). These investigators analyzed nine randomized, placebo-

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FIGURE 5 Effect sizes (mean differences in outcome divided by the pooled standard deviation) in nine studies of the use of antibiotics for exacerbations of COPD. Horizontal lines denote 95% confidence intervals. The data indicate a significant improvement due to antibiotic therapy. (From Ref. 34.)

controlled trials published between 1957 and 1992. Unfortunately, there was not a single common outcome reported in each of the studies included in this analysis. However, some outcomes that were available for analysis and comparison in many of the studies include (1) the mean number of days of illness, (2) the overall symptom score, and (3) the changes in peak expiratory ﬂow rate. Using this form of analysis, there was an overall, statistically signiﬁcant beneﬁt for the antibiotic-treated patients. Analysis of the studies that provided data on expiratory ﬂow rates, noted an improvement of 10.75 L/min in the antibiotic-treated groups. The authors conclude that this antibioticassociated improvement is likely to be clinically signiﬁcant; particularly in patients with low baseline peak ﬂow rates and limited respiratory reserve. There are additional potential beneﬁts of antibiotic therapy for patients with AECOPD. Antibiotics can reduce the burden of bacteria in the airway [37]. Bronchoscopic studies, using sterile protected specimen brush, have demonstrated that approximately 25% of stable COPD patients are colonized (usually V103 organisms) with potentially pathogenic bacteria [38,39]. However, a much larger percentage (50–75%) [39–42] of patients with acute exacerbations have potentially pathogenic microorganisms in addition to signiﬁcantly higher concentrations (frequently z104 organisms) of bacteria in the large airways. Because treatment with appropriate antibiotics signiﬁcantly

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decreases the bacterial burden (and frequently eradicates the organisms that are sensitive) at the 72-hour follow-up bronchoscopy, it is speculated that the proper choice of antibiotic reduces the risk of progression to more severe infections, such as pneumonia [42]. The eradication of bacteria by antibiotics is thought to break the vicious circle of infection (i.e., lung destruction leading to progression of the lung disease). Another study that reports similar ﬁndings of gram-negative pathogens is a prospective, randomized, double-blind, placebo-controlled trial evaluating the use of oﬂoxacin in 90 consecutive patients with AECOPD who required mechanical ventilation, which was recently published by Nouira et al. [43]. These authors demonstrated a signiﬁcant number of gram-negative organisms (including E. coli, P. mirabilis, and P. aeruginosa) in their study population of patients with severe AECOPD. In addition to supporting the ﬁndings of the previously reported studies, this trial demonstrated that treating these pathogens is important for improving outcomes in this high-risk population. The antibiotic-treated group had a signiﬁcantly lower in-hospital mortality rate (4% vs. 22%, P = 0.01) and signiﬁcantly reduced length of stay in the hospital (14.9 vs. 24.5, P = 0.01) compared with the placebo group. In addition, the patients receiving oﬂoxacin were less likely to develop pneumonia than those on placebo, especially during the ﬁrst week of mechanical ventilation (mean F standard deviation: 7.2 F 2.2 days [range 4–11] vs. 10.6 F 2.9 days [range 9–14], P = 0.04 by log-rank test). If the use of antibiotics to treat AECOPD has all the potential beneﬁts discussed, does it matter which agent is chosen? In the Anthonisen et al. study [35], the assumption was made that all of the antibiotics were equivalent; thus, the speciﬁc agent prescribed was not considered important. Moreover, most of the recently published antibiotic trials were designed to compare a new antibiotic with an established compound for the purpose of new product registration and licensing. Equivalence is the desired outcome of such trials, and therefore the agent chosen for comparison is not considered important. In addition, these trials frequently include patients with poorly deﬁned disease severity (often without any obstructive lung disease) and acute illness of minor severity. Another problem with interpreting the literature on AECOPD is the large variation in time frame (48 hours to 28 days) that is used to assess patients for relapse (or the resolution of symptoms) [43–46]. ‘‘Relapse’’ can most clearly be deﬁned as treatment failure resulting in a return visit due to persistent or worsening symptoms [44]. However, many of these patients do not seek medical care, despite persistent symptoms. The published relapse rates for patients with AECOPD range from 17% to 32%. Despite the problems with many of the published antibiotic trials, there are some retrospective trials that emphasize the importance of choosing the correct antibiotic for treatment of patients with AECOPD. A recent retrospective

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study of outpatients with documented COPD, conducted at our institution, evaluated the risk factors for therapy failure at 14 days after an acute exacerbation [47]. The participating patients had a total of 362 exacerbations over an 18-month period. One group received antibiotics (270 visits) and the second group (92 visits) did not. Both groups had similar demographics and severity of underlying COPD. The patients’ mean age was 67 F10 years (FSD), 100% of patients had a greater than 50 pack-per-year smoking history, and 45% were active smokers. Based on the American Thoracic Society’s COPD classiﬁcation, 39% had mild disease, 47% moderate disease, and 14% severe disease. The majority (95%) with severe symptoms at presentation (type 1) received antibiotics, versus only 40% with mild symptoms. The overall relapse rate (deﬁned as a return visit with persistent or worsening symptoms within 14 days) was 22%. After an extensive multivariate analysis, the major risk factor for relapse was lack of antibiotic therapy (32% vs. 19%, P < 0.001 compared to the antibiotic-treated group). The type of antibiotic used was also an important variable associated with the 14-day treatment failure. Patients treated with amoxicillin had a 54% relapse rate compared with only 13% for the other antibiotics (P < 0.01). Furthermore, treatment with amoxicillin resulted in a higher incidence of failure, even when compared with those who did not receive antibiotics (P = 0.006) (Fig. 6). Other variables, such as COPD severity, types of exacerbation, prior or concomitant use of corticosteroids, and current use of chronic oxygen therapy were not signiﬁcantly associated with the 14-day relapse. This study

FIGURE 6 Acute exacerbations of chronic obstructive pulmonary disease: 14-day relapse rates after treatment with or without antibiotics. (From Ref. 47.)

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showed that the use of antibiotics was associated with a signiﬁcantly lower rate of therapy failure. In contrast to Anthonisen’s data [27], our data show that antibiotics are beneﬁcial regardless of the severity of AECOPD (i.e., those with mild AECOPD still gained beneﬁt from treatment with antibiotics). Furthermore, the patients who received antibiotics and whose treatment failed within 14 days had a signiﬁcantly higher rate of hospital admissions than those who did not receive antibiotics. Although there may be many explanations for these treatment failures, the most likely is that the pathogens were resistant to amoxicillin. Recently Destache et al. reported the impact of antibiotic selection, antimicrobial eﬃcacy, and related cost in AECOPD [48]. This study was a retrospective review of 60 outpatients from a pulmonary clinic of a teaching institution who had the diagnoses of COPD and chronic bronchitis. The participating patients had a total of 224 episodes of AECOPD requiring antibiotic treatment. The antibiotics were arbitrarily divided into three groups: ﬁrst-line (amoxicillin, co-trimoxazole, erythromycin, and tetracycline), second-line (cephradine, cefuroxime, cefaclor, cefprozil), and thirdline (amoxicillin-clavulanate, azithromycin, and ciproﬂoxacin) agents. The failure rates were signiﬁcantly higher (at 14 days) for the ﬁrst-line compared with the third-line agents (19% vs. 7%, P < 0.05). When compared with those who received the ﬁrst-line agents, the patients treated with the third-line agents had signiﬁcantly longer time between exacerbations (34 weeks vs. 17 weeks P < 0.02), overall fewer hospitalizations (3/26 [12%] vs. 18/26 [69%] patients, P < 0.02), and considerably lower total cost ($542 vs. $942, P < 0.0001) (Table 1). Based on the results of these studies, in addition to widespread reports of increasing antimicrobial resistance to the common pathogens isolated in patients with AECOPD, appropriate antibiotic selection is extremely important. Therefore, it is not only essential to treat these patients with antibiotics, it is actually critical to choose the appropriate one. END POINT FOR THE TREATMENT OF AECOPD Conventional end points for eﬃcacy of antibiotics treatment in AECOPD include symptom and bacteriological resolution measured at 2 to 3 weeks after the treatment was started. Most of these end points rely solely on the subjective report of symptom improvement. These end points have been used for drug registration purposes but lack clinical relevance [49]. It has been suggested by several reports that the infection-free interval (i.e., the time to next episode of AECOPD) may be a more suitable end point in this patient population [50–52]. Recently, Wilson et al. [53] showed a signiﬁcant increase in the infection-free interval in patients with AECOPD treated with gemi-

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ﬂoxacin as compared with clarithromycin. This end point may reﬂect the ability of the antibiotic to achieve adequate bacteriologic eradication of the airway. This study showed that this end point was associated with decreased hospitalization rates, so this can be translated into cost savings, improved quality of life, and potentially slower progression of the underlying airway obstruction. CLINICAL PARAMETERS FOR STRATIFYING PATIENTS INTO RISK GROUPS Since the morbidity and mortality rates of AECOPD are high, many investigators have attempted to describe characteristics that could be used to riskstratify patients with AECOPD. Some studies have validated a few of the following risk factors for treatment failure; others show diﬀerent factors associated with increased risk of relapse. Despite these conﬂicting studies [43– 46], the clinical parameters that are implicated as possible risk factors for treatment failure in AECOPD include (1) older age (>65 years old), (2) severe underlying COPD (FEV1<35% predicted), (3) frequent exacerbations (z4/ year), (4) more severe symptoms at presentation (Anthonisen et al. [27] types 1 [severe] and 2 [moderate]), (5) comorbidities (especially cardio/pulmonary disease, but also congestive heart failure, diabetes mellitus, chronic renal failure, and chronic liver disease), and (6) prolonged history of COPD (>10 years). Some authors state that many infections in AECOPD are noninvasive and will eventually resolve spontaneously [30,31]. However, because the costs of failed treatment remain high, better strategies are needed for the treatment of these exacerbations. Niederman et al. recently reported that age older than 65 years and inpatient treatment are the major determinants contributing to the overall cost of AECOPD [54]. The cost was estimated at $1.2 billion for the 207,540 inpatients 65 years of age and older versus only $452 million for 5.8 million outpatients in the same age group. The mean length of stay was longer, and the in-hospital mortality rate was signiﬁcantly higher for those older than 65 years of age (Table 2). Based on the concept of risk-stratiﬁcation of patients by clinical parameters, a target approach for the treatment of AECOPD has been proposed by the Canadian Respiratory Society [20]. This group developed a classiﬁcation for patients presenting with symptoms of acute bronchitis using the following factors: (1) number and severity of acute symptoms, (2) age, (3) severity of airﬂow obstruction (measured by FEV1), (4) frequency of exacerbations, and (5) history of comorbid conditions. This symposium suggested that patients could be adequately proﬁled into diﬀerent categories. Acute bronchitis (group 1) includes healthy people without previous respira-

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TABLE 2

Anzueto and Adams Cost of Treatment of Acute Exacerbation of Chronic

Bronchitis Age group

Hospital costs (millions of dollars)

Outpatient costs (millions of dollars)

z65 years <65 years All ages

1141 408 1549

34 14 48

Source: Ref. 54.

tory problems. ‘‘Simple’’ AECOPD (group 2) includes those patients whose age is less than 65 years, those who have had 4 or fewer exacerbations per year, those with minimal or no impairment in lung function (by pulmonary function tests), and those without any comorbid conditions. ‘‘Complicated’’ AECOPD (group 3) includes patients older than 65 years, those with FEV1 less than 50% predicted, or those with 4 or more exacerbations per year.

TABLE 3 Patient Proﬁles from the Canadian Chronic Bronchitis Guidelines Acute bronchitis (group 1) Healthy people without previous respiratory problems ‘‘Simple’’ chronic bronchitis (group 2) Age V 65 years old and <4 exacerbations per year and Minimal or no impairment in pulmonary function and No co-morbid conditions ‘‘Complicated’’ chronic bronchitis (group 3) Age > 65 years old or FEV1 < 50% predicted or z4 exacerbations per year ‘‘Complicated’’ chronic bronchitis with co-morbid illness (group 4) Above criteria for group 3, plus: Congestive heart failure or Diabetes or Chronic renal failure or Chronic liver disease or Other chronic disease Source: Ref. 20.

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Finally, ‘‘complicated’’ AECOPD with associated comorbid illnesses (group 4) includes patients with congestive heart failure, liver disease, diabetes, or chronic renal failure (Table 3). CHARACTERISTICS OF THE ‘‘IDEAL’’ ANTIBIOTIC FOR THE TREATMENT OF AECOPD Characteristics of the ‘‘ideal’’ antibiotic that are important to consider when choosing these agents for patients with AECOPD include: 1. Signiﬁcant activity against the most common pathogens isolated in patients with AECOPD and whether there are substantial gaps in the coverage of these organisms. 2. Adequate coverage of the most likely pathogens in patients with AECOPD based on patient proﬁles that deﬁne the most likely spectrum of etiologic pathogens. As previously described, this is especially important in patients with severe underlying obstructive lung disease, who are more commonly infected with gram-negative organisms than those with mild COPD. In addition, patients with risk factors for a more complicated course (those in group 3 [‘‘complicated’’] and group 4 [‘‘complicated’’ with comorbid conditions]) should be prescribed antibiotics with adequate coverage for the usual pathogens in AECOPD, as well as for gram-negative organisms. Our recommendations from patient stratiﬁcation and treatment are summarized in Table 4. 3. Susceptibility of the antimicrobial agent to the likely pathogens in AECOPD. There is an increasing prevalence of H. inﬂuenzae and M. catarrhalis that produce bacterial enzymes that inactivate traditional h– lactam antibiotics [55,56]. In addition, a growing number of these organisms are resistant to many of the antibiotics that are currently available [57]. It is important to know which of the mechanisms of resistance of these agents are clinically important for the treatment of AECOPD. It is also critical to know the local resistance rates of these microorganisms prior to prescribing a speciﬁc antibiotic for therapy. Please see Chapter 2 for a thorough discussion on resistance of these organisms to many of the antibiotics that are commonly used to treat AECOPD. 4. Good penetration into sputum, bronchial mucosa, and epithelial lining. The goal of antimicrobial therapy is to deliver the appropriate drug to the speciﬁc site of infection. In AECOPD, the bacteria are predominantly found in the airway lumens, along the mucosal cell surfaces, and within the mucosal tissue. Various antibiotic classes exhibit markedly diﬀerent degrees of penetration into the tissues and secretions of the respiratory tract (Table 5) [58,59]. Although there are no studies that demonstrate the concentration

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TABLE 4

Anzueto and Adams Our Recommendations for Antibiotic Therapy

Category Acute bronchitis (group 1) ‘‘Simple’’ AECOPD (group 2)

‘‘Complicated’’ AECOPD (groups 3 & 4)

Probable pathogen

Oral therapy

Viral Haemophilus spp. (H. influenzae), M. catarrhalis, S. pneumoniae, Atypical organisms (possibly) As above, with the possible addition of Pseudomonas spp, Enterobacteriaceae, and other gram-negative organisms

Symptomatic Doxycycline or newer macrolide (azithromycin/clarithromycin) or newer cephalosporins

Fluoroquinolonesa Amoxicillin-Clavulanate

a If at risk for Pseudomonas infection, use ciprofloxacin. Source: Refs. 20 and 126.

of antibiotics at one particular intrapulmonary site is better than any other site, the concentrations of antibiotics in sputum, bronchial mucosa, epithelial lining ﬂuid, and macrophages are thought to be predictive of clinical eﬃcacy (Table 5). These antibiotics exhibit a concentration-eﬀect relationship. 5. Easy to take with minimal side eﬀects. In a recent survey, patient compliance was demonstrated to be signiﬁcantly improved when medications were given once or twice a day, rather than three or more times [60]. In addition, shorter courses of therapy (<14 days) were associated with better compliance. Of the patients interviewed, more than 80% stated a preference for once- or twice-daily dosing and more than 54% admitted to noncompliance with the prescribed regimen (taking the antibiotic sporadically or not completing the full course). 6. Cost-eﬀective, considering more than acquisition cost of antibiotics. It is clear that multiple factors should be considered when selecting an antibiotic for the treatment of AECOPD, in addition to just the acquisition cost. These other economic end points are important when deﬁning the costeﬀectiveness of any particular antibiotic, such as: (1) the cost of treatment failures (including the need for further antibiotics and the days of lost work), (2) the amount saved by preventing hospitalization, (3) the duration of disease-free intervals, and (4) the development of antimicrobial resistance. Although there is not adequate cost-eﬀectiveness data currently available to support the use of any particular antibiotic, the importance of these factors is

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TABLE 5 Percentage of Serum Concentrations of Antibiotic Achieved in Sputum, Epithelial Lining Fluid (ELF), and Bronchial Mucosa Antibiotic PCN Amoxicillin Piperacillin Ceph Cefixime Ceftazidime Cefuroxime Doxycycline Macrolides Erythromycin Azithromycin Clarithromycin Quinolones Ciprofloxacin Gatifloxacin Sparfloxacin Moxifloxacin Aminoglyc Amikacin Gentamicin Tobramycin

Sputum

ELF

Bronchial mucosa 13%

10–14%

40% 27–40% 34–36% 51%

2–15% 14% 18% 5%

114% 3200–5700% 3900–10,300%

200% 125%

140–185% 170% 1250% 870%

240% 170% 360% 170%

10% 20% 50%

PCN = Penicillin. Ceph = Cephalosporins. Aminoglyc = Aminoglycosides. Source: Refs. 58 and 59.

supported by the retrospective studies (previously discussed) by Destache et al. [48] and Niederman et al. [54]. INDIVIDUAL ANTIBIOTIC AGENTS The six characteristics described above for selecting the ‘‘ideal’’ antibiotic are outlined below for each of the major classes of antibiotics prescribed for the treatment of AECOPD. Penicillins This group of antibiotics was one of the ﬁrst classes used for treatment of patients with AECOPD. The medications in this class include amoxicillin and amoxicillin/clavulanate (AugmentinR). Amoxicillin was previously one of the most commonly prescribed antibiotics for AECOPD, but the development of

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h-lactamase by H. inﬂuenzae and M. catarrhalis currently limits their usefulness. Amoxicillin has been shown to be eﬀective therapy (in early studies) for those with mild AECOPD; however, it is not currently recommended unless the local resistance rates are monitored closely and are very low. Dosing of this agent is t.i.d. or q.i.d., which also decreases its usefulness due to compliance issues. In contrast, Augmentin is dosed b.i.d. or t.i.d., has a much wider spectrum of activity (including gram-negative organisms), and is eﬀective against h-lactamase–producing organisms. Despite limited data available regarding the activity of this antibiotic on penicillin-resistant S. pneumoniae [57], Augmentin is most useful for patients with AECOPD in Groups 3 and 4 [20]. The pharmacokinetically enhanced formulation of amoxicillin/clavulanate (2000/125 mg) was designed to achieve high levels of amoxicillin over the dosing duration to eradicate isolates of S. pneumoniae with amoxicillin MICs of 4 Ag/ml or less. A recent study showed that this combination was at least as eﬀective clinically and bacteriologically and was as well tolerated as levoﬂoxacin in the treatment of AECOPD [61]. The side eﬀects of these two agents are similar and primarily involve gastrointestinal symptoms (especially diarrhea). The acquisition cost of amoxicillin is very low; however, the overall cost is probably much higher in some institutions due to the signiﬁcant numbers of treatment failures [47]. The currently approved FDA drugs include amoxicillin 500–750 mg t.i.d. or q.i.d. and AugmentinR 125/500 mg t.i.d. or 500/875 mg b.i.d. 10 days; the 125/2000 formulation is pending approval by the FDA. Cephalosporins Despite their relatively poor activity and suboptimal respiratory pharmacokinetics, the ﬁrst-generation cephalosporins have been used extensively in the management of AECOPD [17]. Two antibiotics from this group (cephalexin and cefaclor) have been shown to be ineﬀective in severe infections and are probably not the best choice for the treatment of AECOPD. The newer cephalosporins (especially third-generation) may have some advantages of improved eﬃcacy and safety and may be used as an option for the treatment of patients in group 2 [20]. FDA-approved drugs from this group include a 10day course of cefprozil (CefzilR) 250/500mg b.i.d., cefuroxime axetil (CeftinR) 250/500 mg b.i.d., loracarbef (LorabidR) 400 mg b.i.d., ceﬁxime (SupraxR) 200/400 mg b.i.d. or q.d., cefpodoxime proxetil (VantinR) 100/200 mg b.i.d., and ceftibuten (CedexR) 400 mg q.d. Trimethoprim-Sulfamethoxazole This antibiotic became very popular in the late 1970s, most likely due to enhanced compliance with the b.i.d. regimen. Many of the early comparison

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studies against cephalosporins and amoxicillin did not demonstrate any signiﬁcant diﬀerences; however, these trials were performed prior to the marked increases in antimicrobial resistance [17]. Currently, the penicillinresistant strains of S. pneumoniae and other common pathogens are highly resistant to these drugs [20,56]. There have also been concerns about the toxicities of trimethoprim-sulfamethoxazole, including acute renal insuﬃciency and the risk of severe skin reactions (particularly in elderly patients). Because many of the new agents available today have fewer side eﬀects as well as potentially enhanced activity, there has been a dramatic decline in the usefulness of this compound. Tetracycline This group of antibiotics includes a naturally occurring molecule (tetracycline) and semi-synthetic molecules (doxycycline and minocycline). Several of the early studies with tetracycline (performed in the 1960s and 1970s) concluded that these antibiotics were eﬀective in the treatment of AECOPD. However, the more recent studies have shown that tetracycline has poor activity against H. inﬂuenzae as well as many of the other commonly isolated organisms in these patients. In contrast, doxycycline (VibramycinR/DoryxR) has been found to be especially active against M. catarrhalis, and minocycline is more active against H. inﬂuenzae and S. pneumoniae. Other advantages of these semisynthetic antibiotics include better oral absorption and a prolonged half-life, which allows for twice-daily dosing [62]. The sputum concentrations are lower for doxycycline than for minocycline. Despite these diﬀerences in the pharmacokinetic properties, Maesen et al. [63], in a randomized, doubleblind prospective study, demonstrated that there were no signiﬁcant differences in the response rates between doxycycline and minocycline in the treatment of AECOPD. The most important limitation to the widespread use of this class of drugs is the increasing emergence of microbial resistance. This class of antibiotics is useful in patients who have allergies to other medications and for treatment of patients in group 2 (‘‘simple’’ AECOPD). Macrolides Erythromycin, a macrolide derived from Streptomyces, inhibits RNAdependent protein synthesis by reversibly binding to the 50S ribosomal subunit of susceptible microorganisms. Azithromycin, clarithromycin, and dirithromycin are semisynthetic derivatives of erythromycin (Table 6). These ‘‘advanced’’ macrolides have signiﬁcantly better tissue penetration and pharmacokinetics as a result of structural modiﬁcations [64,65]. The in vitro activity of macrolides against respiratory pathogens is shown in Table 7 [64,66]. Of the macrolides, erythromycin has the lowest in vitro activity

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TABLE 6

Anzueto and Adams Pharmacokinetic Comparison of Macrolides

Variable Intravenous form Gastrointestinal intolerance Feeding affects absorption Drug interactions (hepatic c P450) Prolonged tissue level

Erythromycin

Clarithromycin

Azithromycin

Dirithromycin

Yes Yes

No No

Yes No

No No

Yes

No

No

No

Yes

Yes

No

No

No

Yes

Yes

Yes

c P450 = cytochrome P450 system. Source: Ref. 64.

against H. inﬂuenzae, whereas azithromycin has the highest. Due to the predominance of this organism in AECOPD, erythromycin should not be used to treat this condition. As previously discussed, the rates of antimicrobial resistance have increased signiﬁcantly over the past few years. The patterns of macrolide resistance are complex and involve at least two mechanisms [67]. One involves an alteration in ribosomal targets (ribosomal methylase [ermAM]) of the bacteria, which is known to result in true clinical resistance. The second mechanism is more prevalent (>75%) and involves the organism actively pumping the macrolide out of the cell (macrolide eﬄux [mefE] mutant strains). Waites et al. found that resistance of S. pneumoniae strains to clindamycin predicted a high level of resistance to clarithromycin, mediated

TABLE 7

Microbiology: In Vitro Activity of Respiratory Pathogens to Macrolides (MIC90) Erythromycin

Streptococcus pneumoniae PCN S 0.016–0.25 PCN R >32 H. influenzae 2–32 Moraxella catarrhalis 0.06–2.0 Chlamydia pneumoniae 0.25

Clarithromycin

Azithromycin

Dirithromycin

V0.008–0.12 >8 2–16 0.03–1.0 <0.1

0.016–0.06 >32 0.5–4.0 V0.016–0.05 0.25–2

N/A N/A 8–16 0.25–1.0 0.5

PCN S = Penicillin-sensitive strains. PCN R = Penicillin-resistant strains. Data: MIC90 = minimum concentration to inhibit 90% of isolates. Ranges are due to the different values reported. Source: Refs. 64 and 66.

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by ermAM (true resistance) [68]. However susceptibility to clindamycin in the strains that were resistant to clarithromycin indicated a lower level of eﬄuxbased resistance, mediated by mefE. It is not known if these mefE strains actually result in clinical resistance, because treatment failures are uncommon in patients treated with these ‘‘advanced’’ macrolides [69,70]. Gotfried et al. [69] found no signiﬁcant diﬀerences in the clinical outcomes of patients at their institution who were infected with macrolide-resistant S. pneumoniae compared with macrolide-sensitive strains. In another publication, Gottfried [70] examined several studies involving the eradication rate of S. pneumoniae in patients treated for AECOPD. Although approximately 15% of the pneumococcal isolates were resistant to clarithromycin in vitro, the bacteriologic eradication rate was between 91% and 93% for the clarithromycintreated patients. Therefore, the reported increases in the prevalence of in vitro resistance of S. pneumoniae to the ‘‘advanced’’ macrolides do not appear to be associated with a proportional rise in the rate of clinical failures. The dosing of the macrolides varies among the diﬀerent antibiotics. Erythromycin must be given every 6–8 hr (usually for a 10-day course). Both azithromycin and dirithromycin are given only once a day and are eﬀective with dosing regimens of 3 to 5 days [64,70]. Direct comparison of azithromycin (3-day course) and clarithromycin (10-day course) showed no diﬀerence in response rate or adverse reactions [71]. A recent study with the new extended-release preparation of clarithromycin has been shown to be eﬀective when given once a day for 5 to 7 days [72]. In general, macrolides are safe antibiotics. Treatment with erythromycin often results in signiﬁcant gastrointestinal symptoms, including nausea, vomiting, abdominal cramps, and diarrhea. This drug also has signiﬁcant interaction with drugs that are metabolized in the liver via the P450 enzyme system [64]. The newer-generation macrolides are better tolerated, have minimal gastrointestinal symptoms, and fewer drug interactions. However, clarithromycin has a distinctive taste perversion that is less common with the extended-release preparation. FDA-approved macrolides to treat AECOPD include erythromycin 250/500 mg every 6–8 hr 10 days; clarithromycin (BiaxinR) 250/500 mg b.i.d. 10 days, or two 500 mg tablets once daily for 7 days; azithromycin (ZithromaxR) 500 mg on day 1, then 250 mg q.d. on days 2–5; and dirithromycin (DynabacR) 500 mg a day 5 days. Fluoroquinolones The ﬂuoroquinolones are extremely potent and oﬀer broad-spectrum coverage against the most common organisms in patients with AECOPD (Table 8). Some of the more recently developed quinolones have enhanced activities against many gram-positive species (i.e., S. pneumonia), atypical pathogens

238

TABLE 8

Anzueto and Adams Fluoroquinolone Activity Against Common Respiratory Pathogens

(MIC90) Pathogen

Ciprofloxacin

Levofloxacin

Gatifloxacin

Moxifloxacin

S. pneumoniae PCN S PCN R H. influenzae M. catarrhalis C. pneumoniae

0.5–3.13 2 2 0.015–4.0 0.015–0.1 2–4

1.0–3.13 1–2 1–2 0.03 0.06–0.12 0.25

0.06–1 0.06–0.25 0.06–0.25 0.004–0.016 0.004–0.03 0.06–0.5

0.03–0.25 0.06–0.12 0.06–0.12 0.008–0.06 0.004–0.03 0.06

PCN S = Penicillin-sensitive strains. PCN R = Penicillin-resistant strains. Data: MIC90 = minimum concentration required to inhibit 90% of isolates. Ranges are due to the different values reported. Source: Refs. 56,57,78, and 79.

(i.e., Chlamydia pneumoniae, Mycoplasma pneumoniae, and Legionella pneumophila), and anaerobes [73]. The quinolones have a unique mechanism of action in that they interfere with bacterial replication by inhibiting enzymes (called topoisomerases) that are responsible for maintaining bacterial DNA supercoiling [74]. Although four types of topoisomerases exist, only two of these are targeted by the quinolones: (1) topoisomerase IV and (2) DNA gyrase. The bactericidal activity against gram-positive bacteria is primarily a result of the quinolones targeting topoisomerase IV, whereas the activity against gram-negative organisms involves DNA gyrase [75]. The overall resistance rates of the quinolones have remained low among communityacquired respiratory pathogens but have increased among nosocomial pathogens. The three known mechanisms involved in the development of quinolone resistance include (1) mutational changes in microbial DNA topoisomerases, (2) selected alterations in bacterial outer membrane proteins, and (3) the development of a highly active eﬄux system (that pumps the antibiotic out of the cell) [76]. As a group, the quinolones are concentrated intracellularly in most tissues, including the sputum, the epithelium lining ﬂuid, and the bronchial mucosa (Table 5). They also have favorable clinical pharmacokinetics including low serum protein binding (which allows the majority of the drug to diﬀuse freely into the extravascular space), high oral bioavailability (>90%), and a prolonged half-life (>8–12 hours) [77–79]. Another important characteristic of the quinolones is the signiﬁcant post-antibiotic eﬀect (PAE), which results in continued suppression of an organism’s growth after short exposure to the antimicrobial agent [80]. Most of the newer quinolones exhibit PAEs of 1–6 hours and may be important in preventing the emergence of resistance.

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The eﬃcacy of the quinolones in the treatment of AECOPD has been demonstrated in multiple clinical trials. Ball et al. [76] summarized the early clinical trials comparing individual quinolones with other antibiotics that are frequently used for these lower respiratory tract infections. The majority of these studies demonstrated clinical eﬃcacy rates (as well as bacterial eradication rates) of greater than 90%. The studies involving the most recently approved agents in this class of antibiotics (gatiﬂoxacin and moxiﬂoxacin) also demonstrate similar rates of clinical success [74,81]. Recent reports have shown the eﬃcacy of shorter course of therapy (5 days) with the new ﬂuoroquinolones [82]. A useful classiﬁcation of the quinolones is by ‘‘generations,’’ which allows for diﬀerentiation of their antibacterial spectrums of activity [76,83]. Modiﬁcations of the side chains of the quinolone rings are responsible for these diﬀerent clinical spectrums and adverse side eﬀects. The new generation quinolones (gatiﬂoxacin, moxiﬂoxacin) are the more potent agents against S. pneumoniae and anaerobe organisms [74]. In general, the quinolones are well tolerated and have an adverse event rate of approximately 4–5% [81]. These adverse eﬀects, which are generally mild and transient, include rash, dizziness, headache, gastrointestinal disturbances (usually nausea, vomiting, dyspepsia, diarrhea, abdominal pain, etc.), and minor hematological abnormalities. The gastrointestinal side eﬀects of the quinolones are usually not as severe and frequent as those associated with macrolides or with amoxicillin/clavulanate. Some drugs that are not available were associated with severe phototoxic reactions, disturbing metallic taste and liver toxicity. Quinolones have also been associated with a prolonged QTc interval but thus far have not resulted in adverse clinical outcomes [84]. The FDA recommends that all quinolones be avoided in patients receiving class IA or class III antiarrhythmic agents, in patients with known prolongation of the QTc interval, and in those with uncorrected hypokalemia. The two major types of drug interactions involving this group of antibiotics include a reduction in gastrointestinal absorption of the quinolones and alterations in the metabolism of other drugs. Many medications that contain multivalent cations (such as antacids containing magnesium or aluminum, sucralfate, iron, zinc, and calcium) appear to signiﬁcantly reduce the absorption of all the quinolones. Therefore, these agents should be dosed at least 2–4 hours before or after the administration of these antibiotics [85]. Many of the quinolones cause alterations in other medications via the hepatic cytochrome P450 system. When administered concomitantly, these agents may lead to an increase in the concentration of theophylline, warfarin, and caﬀeine. FDA-approved and currently available drugs from this group include ciproﬂoxacin (CiproR) 500/750 mg b.i.d. 10 days, gatiﬂoxacin (TequinR) 400 mg q.d. 10 days, levoﬂoxacin (LevaquinR) 500 mg b.i.d. 10 days,

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moxiﬂoxacin (AveloxR) 400 mg q.d. 5 days, and oﬂoxacin 400 mg b.i.d. 10 days. BRONCHODILATOR THERAPY Bronchodilator drugs are the primary therapeutic interventions in patients with AECOPD (Table 9). Unfortunately there are no clearly deﬁned objective end points that can routinely be use to assess the patient’s improvement. The end point that most investigators use is improvement in symptoms. Other parameters, such as improvement in physical ﬁndings or pulmonary functions tests, are more variable. Evidence does not support online measurement of FEV1 during an exacerbation [12,86–88]. The bronchodilators used to treat acute exacerbations of chronic obstructive lung disease are short-acting h-2 agonists, long-acting h-2 agonists, and anticholinergic agents [88–94]. The clinical studies available have shown that short-acting h-2 agonists and ipratropium bromide are equally eﬃcacious during acute exacerbations. While some studies suggest that adding ipratropium bromide to a short- or long-acting h-2 agonist improves the patient’s spirometry and clinical response [94,95], other studies do not show an improvement in spirometry or clinical symptoms [88,92,95]. The current clinical practice is to use ﬁrst a short-acting h-2 agonist and then ipratropium bromide if the patient’s symptoms do not improve. These agents may be used concomitantly. The inhaled route for delivering these drugs has been shown to result in fewer adverse events and maximum eﬃcacy. Patients can receive metereddose inhalers (MDI) in combination with devices such as large-volume attachments (spacers), breath-attenuated MDI, and dry-powdered inhalers. TABLE 9

Pharmacotherapy for Acute Exacerbations of Chronic Lung Disease

Bronchodilator therapy

Short-acting h-2 agonists, by MDI with spacer

Corticosteroids Oral prednisone therapy, 40 mg p.o. q.d., for 7–10 days Theophylline Due to poor safety profile, its use is not recommended Source: Refs. 90–95, 111, and 113.

Long-acting h-2 agonist. Ipratropium bromide, Salmeterol ! AECOPD MDI alone or in combination with short-acting h-2 agonist If the patient cannot tolerate p.o. therapy, short course of I.V. Solu-Medrol

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The techniques for using MDI and their attachments must be taught to the patients and reinforced [96]. Drug deposition may vary among delivery systems. Nebulization has been a preferred mode to deliver bronchodilators during acute exacerbation mainly because patients may have diﬃculty using MDI devices. The safety and value of continued drug nebulization delivery has not been established in COPD [97]. Randomized controlled trials comparing MDI with nebulization have not shown the superiority of continuous nebulization therapy [98]. In mechanically ventilated patients, bronchodilator delivery via MDI with a spacer has a higher particle deposition as compared to nebulized [99,100]. The dose scheduled for the h-2 agonists and ipratropium bromide during an acute exacerbation has not been established. There is no evidence that oral or intravenous h-2 agonists improve bronchodilator response; therefore these routes of administration are not recommended. High doses of h-2 agonists are known to be associated with increased side eﬀects, including tachyrhythmias, tremor, and morbidity. Recent studies have described the increased rate of cardiac events associated with h-2 agonists in patients with COPD [101], and failed to show a beneﬁt of regular use of albuterol in stable patients [102]. Short-acting h-2 agonists may be associated with an idiosyncratic bronchoconstriction response and tachyphylaxis with a decrease in the patient’s clinical response [103]. Ipratropium bromide has been demonstrated to have minimal side eﬀects, mainly unpleasant taste and cough. There is no evidence that patients on ipratropium bromide can develop tolerance to chronic therapy [93,103]. Methylxanthines, theophylline, and/or aminophylline have been shown to have comparable or less bronchodilator eﬀect than h-2 agonists or anticholinergic agents [104,105]. The major limitation of these drugs is the need for continuous blood level monitoring [106,107], and their side eﬀects include cardiac arrhythmias, electrolyte imbalances, and extensive drug interactions [106]. Because of the potential for fatal adverse side eﬀects and the need for continuous serum level monitoring, we do not recommend the use of methylxanthines in the treatment of acute exacerbations [106,108]. TREATMENT WITH CORTICOSTEROIDS Corticosteroids are recommended in most cases of AECOPD. There is a consensus that patients with signiﬁcant bronchodilator response are more likely to beneﬁt from this therapy [109], but the precise role or corticosteroids is not well established. Corticosteroids can be administered intravenously, orally, and by inhalation (Table 9). The use of inhaled corticosteroids during acute exacerbations has not been studied. Albert et al. [110] published the ﬁrst randomized, double-blind, placebocontrolled trial of systemic corticosteroids in the treatment of AECOPD.

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FIGURE 7 (A) FEV1 response to corticosteroids and placebo and (B) long-term effect of two doses of corticosteroids and placebos. (From Ref. 113.)

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A regimen of I.V. methylprednisolone four times daily for 3 days produced an early improvement in FEV1 that was observed during the treatment period [110]. Recent studies have suggested that a short course of oral prednisone therapy can be useful [111,112]. A 2-week course of 30 mg daily oral prednisone in patients with severe airﬂow obstruction resulted in a signiﬁcantly lower rate of treatment failure, a decreased length of hospital stay, and a more rapid improvement in FEV1 [111]. In the largest study published to date—the Systemic Corticosteroids in Chronic Obstructive Pulmonary Disease Exacerbations (SCCOPE) study—271 patients with an acute exacerbation of COPD were enrolled [113]. Patients received placebo or a two-dose regimen of corticosteroids therapy for 2 or 8 weeks. For the combined glucocorticoid group, the risk of treatment failure as compared to placebo was reduced by 10 percentage points (33% vs. 23%, respectively), and FEV1 improved statistically signiﬁcantly during the ﬁrst 3 days of therapy. There was no diﬀerence in FEV1 after 2 weeks. The SCCOPE trial demonstrated equivalent outcome between 2-week and 8-week corticosteroid regimens (Fig. 7). Because all the published studies have excluded patients who received systemic corticosteroids within the preceding month, it is not known if corticosteroid treatment is also eﬃcacious in these patients. Inhaled nebulized corticosteroids (budesonide) also improve post-bronchodilator FEV1. Regular use of inhaled corticosteroids may reduce the numbers of yearly exacerbations. The appropriate duration of therapy is in the range of 5 days to 2 weeks. The 10-day course has been studied best. Well-known side eﬀects of systemic corticosteroids are the major limiting factors of this therapy. The SCCOPE trial showed that hyperglycemia was signiﬁcantly more frequent in patients who received corticosteroids compared with placebo [113]. In patients with COPD, corticosteroid-induced myopathy may be more common than was initially appreciated. Histologically, both myopathic changes and generalized muscle ﬁber atrophy have been reported [114]. In one study, survival of patients with steroid-induced myopathy was signiﬁcantly lower compared to those without myopathy, but with similar airﬂow obstruction [114,115].

MUCUS-CLEARING STRATEGIES: EXPECTORANTS, MUCOLYTICS, AND MUCOKINETIC AGENTS In COPD, mucus is generally copious and tenacious and is a major symptom in patients during both stable condition and exacerbations. Current data suggest that pharmacologic mucus-clearing strategies do not shorten the disease course of patients with acute exacerbation or improve FEV1 [116,117].

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We cannot recommend the use of any currently available mucolytic agents during acute exacerbations of AECOPD. PREVENTION The two most important prevention measures are smoking cessation and active immunizations, including inﬂuenza and pneumococcal vaccinations. Active smoking cessation should be included in the therapy of these patients. The annual rate of decline of the forced expiratory volume in 1 second (FEV1) of a smoker is approximately 80 cc/per year. In contrast, the rate decline in FEV1 in nonsmokers is 25 to 30 cc per year [2]. The Lung Health Study showed that in middle-aged patients with normal or mild decrease in lung function, smoking cessation resulted in an improvement in FEV1 after one year. In this study, 35% of patients who stopped smoking after the ﬁrst annual visit registered an increase in mean post bronchodilator FEV1 of 57 mL, whereas patients who continue to smoke experienced a decline in FEV1 mean—38 mL [118]. Cigarettes are among the most addicting products known, and the vast majority of patients who quit smoking relapse within months. Nicotine is the main addictive substance in cigarettes; thus, most patients experience severe withdrawal symptoms when they abruptly stop smoking [119]. The U.S. Department of Health and Human Services has published extensive clinical practice guidelines on smoking cessation [120]. Nicotine replacement therapy is widely used to overcome the patient’s withdrawal symptoms. The use of nicotine replacement therapy should always include behavior modiﬁcation programs to increase the likelihood of success. Recently, it has being demonstrated that some antidepressants, especially bupropion (ZybanR) can be an eﬀective antismoking product [121]. Inﬂuenza is an important cause of lower respiratory tract infections. Inﬂuenza A and B often reach epidemic proportions during the winter months. The impact of inﬂuenza is critical to the development of other lower respiratory tract infections including AECOPD and pneumonia. Epidemiological studies have shown that the frequency of lower respiratory tract infections and their morbidity and mortality are markedly reduced with inﬂuenza vaccination [122] In order to deﬁne the eﬀects of inﬂuenza, and the beneﬁts of inﬂuenza vaccination in elderly persons with chronic lung disease, Nichol et al. [123] conducted a retrospective, multiseason cohort study in a large managed care organization. The outcomes in vaccinated and unvaccinated individuals were compared after adjustment for baseline demographics and health characteristics. This study showed that vaccination rates were greater than 70%. In patients that were not vaccinated, the hospitalization rates for pneumonia and inﬂuenza were twice as high in the inﬂu-

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FIGURE 8 Observed annualized rates of hospitalization for pneumonia and influenza among vaccinated and unvaccinated persons for each study period. (From Ref. 123.)

enza season as they were in the interim (non-inﬂuenza) periods (Fig. 8). The Vaccinated patient group had fewer outpatient visits, fewer hospitalizations, and fewer deaths. Consequently, the inﬂuenza vaccine should be given to patients with COPD. The polyvalent vaccine based on pneumococcal capsule serotypes has been shown to be eﬀective in preventing pneumococcal bacteremia and pneumonia [124]. The available 23-serotype vaccine has been shown to have an aggregate eﬃcacy of more than 60%. Its eﬃcacy tends to decline with age and with worsening of patient immune state [125]. The vaccine is also recommended in patients with COPD. There are no contraindications for use of either pneumococcal or inﬂuenza vaccine immediately after an episode of pneumonia or AECOPD. Vaccines can be given simultaneously without aﬀecting their potency. There are no other vaccines available in adults to prevent lower respiratory tract infections. Vaccines intended to prevent infectious due to nontypable Haemophilus sp. or Pseudomonas sp. are being developed but are not yet available. SUMMARY The cost, morbidity, and mortality related to AECOPD remain unacceptably high, especially in patients with signiﬁcant underlying obstructive lung disease. Because those with AECOPD are a heterogeneous group, it is important to risk-stratify them based on clinical parameters and patient de-

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mographics. As described in detail in this chapter, the use of antibiotics, bronchodilators, and corticosteroids are important components in the management of these patients. In particular, it is essential to administer an appropriate antimicrobial agent from the start of therapy, so that the risks of treatment failure and the morbidity of AECOPD may be minimized [126]. REFERENCES 1.

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13 Treatment of Pneumonia in Nonhospitalized Patients Thomas M. File, Jr. Northeastern Ohio Universities College of Medicine, Rootstown and Summa Health System Akron, Ohio, U.S.A.

INTRODUCTION Community-acquired pneumonia (CAP) is a common disorder that is potentially life-threatening, especially in older adults and those with comorbid disease. However, the majority of patients with CAP have an illness of relatively mild severity and can be safely treated in the ambulatory setting. Clinicians are constantly challenged to treat CAP appropriately and cost-eﬀectively. Although most patients have only mild disease, many clinicians feel uneasy about whether they can be safely treated as outpatients. Over the past decade, numerous guidelines for management of CAP have been published that provide guidance for the stratiﬁcation of patients as well as appropriate processes of care. Recommendations within these guidelines provide direction regarding appropriate management of patients treated as outpatients. 255

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EPIDEMIOLOGY In the United States, approximately 4–5 million cases of community-acquired pneumonia (CAP) occur each year, accounting for 10 million physician visits, approximately 500,000 hospitalizations, and approximately 45,000 deaths [1]. Although mortality has ranged from 2% to 30% among hospitalized patients, mortality is less than 1% for patients who are not hospitalized—which is the large majority of patients. CAP occurs more commonly in children under the age of 5 years and in adults over the age of 65 years. The incidence of CAP for persons between the ages of 5 and 60 years has been reported to be between 100 and 500 per 100,000 population [2]. In a series of studies, Foy and coworkers examined the attack rate of pneumonia by age in a prepaid medical care group that had a population of 180,000 when the study ended in February 1975 [3]. The overall annual rate of pneumonia was 12 per 1,000 population per year. Rates were highest in the 0–4 years of age group at 12 to 18 per 1,000 population. Between the ages of 5 and 60 years, the rate ranged from 1 to 5 per 1,000 population. In 1987, Houston et al. restrospectively evaluated the incidence of pneumonia (nursing home and community-associated) in elderly patients and residents 65 years of age or older in Homestead County, Minneapolis, Minnesota [4]. The overall incidence rate for an initial episode of pneumonia was 3032 per 100,000 population; this rate rose to 7923 per 100,000 population among residents aged 85 or above. In a prospective study of all adult patients (z18 years of age) hospitalized for CAP in two counties in Ohio during 1991 (Ohio Community Based Pneumonia Incidence Study), Marston et al, reported an incidence rate of 280 cases per 100,00 population [5]. The rate was 962 cases per 100,000 for persons older than 65 years of age. In this study, the incidence was higher among blacks than whites and higher among males than females. The incidence of CAP is highest in the winter months and during inﬂuenza epidemics.

PATHOGENESIS OF CAP In a healthy individual, the lower respiratory tract is kept essentially sterile by very eﬀective pulmonary defense mechanisms that include anatomic barriers as well as humoral, cell-mediated, and phagocytic immunity. Although normal individuals commonly aspirate their upper respiratory tract ﬂora, pneumonia develops when there is a breakdown in the pulmonary host defenses, when the invading organisms are virulent, or when a large inoculum size of the microorganism is introduced. Aspiration remains the most common route of acquiring pneumonia. Less commonly, organisms enter the lungs by inhalation, or by a hematogenous or contiguous route.

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The phagocytes play an important role in protecting the host against most pathogens causing CAP. Cell-mediated immunity plays an important role against viruses and intracellular infectious agents such as Mycobacterium, Legionella, and Chlamydia species. Several studies have evaluated risk factors for pneumonia [6–10]. Documented conditions associated with increased risk for pneumonia include increasing age, smoking, alcoholism, asthma, immunosuppression, institutionalization, dementia, seizure disorder, congestive heart failure, peripheral vascular disease, and chronic obstructive pulmonary disease. The elderly appear at increased risk related to a variety of factors such as increased number of underlying conditions, increase hospitalizations, age-related impairments and host-defense mechanisms, and decreased immune response. Several of these risk factors increase the likelihood of aspiration, which is a key factor in the pathogenesis of pneumonia. A common factor that predisposes to CAP is smoking. Cigarette smoke not only causes chronic bronchitis but also impairs local defense mechanisms, thus contributing to damage of the airway. Subsequently, the patient is at an increased risk of experiencing an acute lower respiratory tract infection such as CAP. Overcrowding in institutions is a risk factor for outbreaks of pneumococcal pneumonia. Outbreaks have occurred in jails and nursing homes. When recurrent episodes of bacterial pneumonia occur, the presence of underlying predisposition (i.e., congenital defects, immunoglobulin [IgG] deﬁciency, acquired immunodeﬁciency syndrome) should be considered. CLINICAL MANIFESTATIONS Adult patients who are immunocompetent should be evaluated for pneumonia if they present with symptoms that include cough, sputum production, labored breathing (including altered breath sounds and rales), and/or fever. Other symptoms can include chest pain, myalgia, headache, dyspnea, and fatigue. Many of these symptoms may also be present in patients with upper respiratory tract infections, other lower respiratory tract infections (i.e., acute bronchitis, chronic bronchitis) as well as noninfectious diseases (i.e., reactive airways disease, atelectasis, CHF, vasculitis, pulmonary embolism, and malignancy). An accurate diagnosis of CAP is important because antibiotic therapy is usually indicated for pneumonia but is usually not indicated for most upper respiratory tract infections or acute bronchitis, because most are viral in etiology. Given the potential danger associated with antibiotic overuse (increased bacterial resistance and unnecessary side eﬀects) and the cost of inappropriate therapy, recent guidelines recommend that a chest x-ray be obtained for the routine evaluation of patients with suspected CAP [1,11,12]. The rationale is to appropriately establish the

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diagnosis of pneumonia and diﬀerentiate respiratory illnesses such as acute bronchitis. While it is generally considered that the chest x-ray is necessary to establish a diagnosis of CAP, I acknowledge that in the ‘‘real world’’ many health care providers treat patients on the basis of clinical manifestations only. It is very important to point out, however, that distinguishing CAP from other respiratory illnesses such as acute bronchitis is very diﬃcult on clinical grounds alone. A review of published studies of pneumonia indicates no combination of clinical ﬁndings can reliably deﬁne the presence of pneumonia [13]. Moreover the absence of any vital sign abnormality or any abnormalities on chest auscultation substantially reduces the likelihood of pneumonia. Because pneumonia is therefore very unlikely in the absence of these abnormalities, I recommend a strategy of assigning a diagnosis of CAP without chest x-ray conﬁrmation be considered only if there are signiﬁcant clinical manifestations (i.e., new cough with abnormal vital signs and localized auscultatory ﬁndings). To treat with antibiotics in the absence of these ﬁndings is likely to be associated with the use of these agents for nonbacterial respiratory illnesses (i.e., viral or noninfectious) and contribute to the already high risk of antimicrobial resistance. The clinical course of CAP is variable among patients. In a study of patients with ambulatory CAP, the median time to resolution for fever was 3 days; for myalgia, 5 days, for dyspnea, 6 days; and for both cough and fatigue, 14 days [14]. Symptoms can be expected to last even longer in more seriously ill patients. In another study, Fine et al. found that 86% of patients had one or more persisting pneumonia-related symptom at 30 days [15]. Such information should be imparted to patients for better awareness of their illness and anticipated clinical course. SITE-OF-CARE DECISION: DEFINING LOW-RISK PATIENTS FOR AMBULATORY CARE A key decision facing the clinician is whether to hospitalize the patient with CAP. A general consensus is that approximately 75% of patients can be appropriately treated as outpatients [1]. The initial site-of-care decision has an impact on the extent of diagnostic testing as well as the choice of empirical antimicrobial therapy. The advantages of not hospitalizing patients for CAP are considerable. The cost of inpatient care is up to 20 times higher than that of outpatient care [16]. In addition, most patients indicate a preference for home care if it is considered as safe. In a study conducted by Coley et al. 80% of patients with CAP said they would prefer home care and would be willing to pay an average of 24% of their monthly income to make sure of it [17]. Ambulatory care also avoids many of the iatrogenic complications associated

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with hospitalization. For elder patients, particularly, a reduction in immobilization (i.e., time in a hospital bed) time can facilitate better convalescence. The decision to hospitalize a patient with CAP or to treat as an outpatient depends on many variables, including the severity of illness, associated disease, adequacy of home support, and probability of compliance. Recognized risk factors for increased mortality of patients with CAP include extreme of age, comorbid illnesses (i.e., malignancy, congestive heart failure, coronary artery disease, alcoholism, abnormality of vital signs), and several laboratory and radiographic ﬁndings [10]. The admission decision remains a judgmental one; however, prognostic scoring rules have been developed that provide support for this decision [18,19]. A pneumonia severity of index score, the ‘‘pneumonia prediction rule,’’ has been developed from studies of the pneumonia Patient Outcomes Research Team (PORT), and it can assist clinicians in making the site-of-care

FIGURE 1 Assessing risk in patients with community-acquired pneumonia.

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TABLE 1 Scoring System of the Prediction Rule for Patients Assigned to Risk Classes II through V Patient characteristic Demographic factor Age (male) Age (female) Nursing home resident Comorbid illnesses Neoplastic diseaseb Liver diseasec Congestive heart failured Cerebrovascular diseasee Renal diseasef Physical examination finding Altered mental statusg Respiratory rate z30 breaths/min Systolic blood pressure <90 mmHg Temperature <35jC or >40jC Pulse >125 beats/min Laboratory or radiographic finding Arterial pH<7.35 Blood urea nitrogen >30mg/dL Sodium <130 mEq/L Glucose >250 mg/dL Hematocrit <30% Arterial partial pressure of oxygen <60 mm Hgh Pleural effusion a

Points assigneda

No. of years of age No. of years of age–10 +10 +30 +20 +10 +10 +10 +20 +20 +20 +15 +10 +30 +20 +20 +10 +10 +10 +10

A total point score for a given patient is obtained by adding the patient’s age in years (age-10, for females) and the points for each applicable patient characteristic. Points assigned to each predictor variable were based on coefficients obtained from the logistic regression model used. b Any cancer except basal or squamous cell cancer of the skin that was active at the time of presentation or diagnosed within 1 year of presentation. c A clinical or histologic diagnosis of cirrhosis or other form of chronic liver disease such as chronic active hepatitis. d Systolic or diastolic ventricular dysfunction documented by history and physical examination as well as chest radiography, echocardiography, Muga scanning, or left ventriculography. e A clinical diagnosis of stroke, transient ischemic attack, or stroke documented by MRI or computed axial tomography. f A history of chronic renal disease or abnormal blood urea nitrogen and creatinine value documented in the medical record. g Disorientation (to person, place, or time, not known to be chronic), stupor, or coma. h In Pneumonia Patient Outcome Research Team cohort study, an oxygen saturation value <90% on pulse oximetry or intubation before admission was also considered abnormal. Source: Ref. 18.

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decision [18]. The prediction rule stratiﬁes patients to one of ﬁve categories by using a point system based on several variables. Most of the information needed for scoring is easily available from the history and physical examination. The prediction rule is a two-step process and ﬁrst considers age (over 50), the presence of comorbid conditions, and the presence of abnormal vital signs. If any of these are present, then points are assigned to each condition for which a total score and classiﬁcation can be determined (Fig. 1) (Tables 1,2). This process has been validated as a method for identifying patients at risk for death, and it has been shown to be an eﬀective method for triaging patients and particularly for identifying ‘‘low risk’’ patients who can be safely treated away from the hospital [20–24]. In contrast, the British Thoracic Society guidelines recommend an assessment of severity based on the presence of ‘‘adverse prognostic features’’ [19]. These adverse features include age greater than 50 years; coexisting disease; and four additional speciﬁc ‘‘core’’ features: mental confusion, elevated urea nitrogen, respiratory rate> 30/minute, and low blood pressure, hence CURB. ‘‘Additional’’ adverse prognostic features include hypoxemia and bilateral or multilobe pulmonary inﬁltrates on chest radiograph. Patients who display none of the features listed are at low risk for death and do not normally require hospitalization, whereas those who display two or more ‘‘core’’ adverse prognostic features should be hospitalized. This rule was studied in prospective trial in the United Kingdom and found to correlate well with mortality [25]. Prediction rules may oversimplify the way physicians interpret important variables, and therefore these approaches are meant to contribute to, rather than supersede, physicians’ judgment. Because hypoxemia is an important factor, clinicians are encouraged to use pulse oximetry for assessment of severity and oxygen requirement. In addition, support system outside the hospital, substance abuse, and other factors that may interfere with com-

TABLE 2

Mortality Rates Based on Risk Class as Determined by Prediction Rule Validation cohort

Risk class I II III IV V a

No. of points

No. of patients

Mortality, %

Recommended site of care

—a V70 71–90 91–130 >130

3034 5778 6790 13,104 9333

0.1 0.6 2.8 8.2 29.2

Outpatient Outpatient Outpatient or brief inpatient Inpatient Inpatient

Absence of predictors. Source: Ref. 18.

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pliance should be considered whenever home treatment is contemplated. (For further discussion of CAP severity of illness evaluation, refer to Chapter 14).

ETIOLOGY The etiologic pathogens of CAP have changed in prevalence over time. While S. pneumoniae remains the most common causative pathogen, a number of newer pathogens, such as C. pneumoniae and sin nombre virus (hantavirus), have been recognized in recent years (Table 3). However, prospective studies for evaluating the cause of CAP in adults have failed to identify the cause of 40–60% of cases, and two or more etiologies have been identiﬁed in 2%–5% of cases [26]. The most common etiologic agent identiﬁed in virtually all studies of CAP is Streptococcus pneumoniae. Based on a review of more than 15 published reports from North America that covers more than two decades and from mostly hospitalized patients, the ranges for prevalence of speciﬁc bacterial pathogens as causes of pneumonia are reported as follows: S. pneumoniae 20–60%; H. inﬂuenzae 3–10%; M. pneumoniae 1–6%; C. pneumoniae 4–6%; Legionella species 2–8%; viruses 2–13%; aspiration 6–10%; S. aureus 3–5%; gram-negative bacilli 3–5%; and miscellaneous 10–20% [27]. Few of these studies used techniques to isolate anaerobic bacteria, which may have been identiﬁed in studies using transtracheal aspirates and may account for 20–30% of all cases of CAP. The frequency of other etiologies—for example, Chlamydia psittaci (psittacosis), Coxiella burnetii (Q fever), Francisella tularensis (tularemia), and endemic fungi (histoplasmosis, coccidioidomycosis, blastomycosis)—varies with location. The relative proportion rates for studies evaluating speciﬁc etiologic causes vary depending on the strictness of criteria for diagnosis, age group, geographic location, and whether an epidemic is occurring at the time of evaluation. Therefore, an attempt to compare various studies can be problematic. Specific Etiology and Epidemiological Setting No convincing association has been demonstrated between individual symptoms, physical ﬁndings or laboratory test results, and speciﬁc etiology. However, and although not absolute, certain pathogens cause CAP more commonly among persons with speciﬁc risk factors. The pneumococcus is classically a pathogen of the elderly and patients with a variety of medical conditions, including chronic obstructive lung disease, congestive heart failure, asplenia, immunoglobulin deﬁciency, hematological malignancy, and HIV infection. The incidence of pneumococcal bacteremia is extremely high in newborns and infants up to 2 years of age, low in teenage children and young adults, then increases in elderly adults. Recent

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TABLE 3

Pathogens Associated With Community-Acquired Pneumonia

Traditional pathogens Streptococcus pneumoniae Haemophilus influenzae Mycoplasma pneumoniae Oral anaerobes Gram-negative bacilli (less common) Staphylococcus aureus (less common) Influenza More recently recognized pathogens Legionella species Chlamydia pneumoniae (strain TWAR) Moraxella (Branhamella) catarrhalis Sin nombre virus (hantavirus) Parainfluenza Respiratory syncytial Pathogens with increasing prevalence or epidemiologic factors Mycobacterium tuberculosis Pneumocystis carinii (associated with HIV infection) Less Common pathogens in immunocompetent host Bacteria Neisseria meningitidis Streptococcus pyogenes Alpha-hemolytic streptococci (i.e., S. milleri) Coxiella burnetti (Q fever) Chlamydia psittaci Fungi Histoplasma capsulatum Coccidioides immitis Blastomyces dermatitidis Viruses Influenza Parainfluenza Adenovirus Respiratory syncytial Varicella Less common pathogens in immunocompromised host Bacteria Nocardia species Mycobacterium species (i.e., avium complex) Fungi Aspergillus species Candida species Cryptococcus species Rhizopus species Viruses Herpes simplex Cytomegalovirus Toxoplasma species

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studies continue to document the emergence of drug-resistant S. pneumoniae (DRSP). The emergence and rapid accumulation of DRSP isolates has posed a new challenge for practitioners. Legionella infection has a varied epidemiological picture. Cases can occur in clusters or sporadically from the community or in the hospital setting. It appears there is geographic variance of incidence, because more cases are reported from the north central and northeastern regions of the United States; however, some of this variation may depend on the extent of diagnostic testing [28]. There also may be local environmental factors that are important and still not well deﬁned. In a controlled study of risk factors associated with Legionella pneumonia, Straus et al. observed the following as predisposing conditions: recent travel with an overnight stay, stay outside the home, recent domestic plumbing, renal or liver failure, smoking, diabetes, systemic malignancy, and other immunosuppressive states [29]. Water is the major reservoir; organisms can be found in freshwater environments worldwide. Legionella can also be isolated from moist soil. Transmission to humans occurs when water containing the organism is aerosolized in respiratory droplets (1–5 Am in diameter) and inhaled or aspirated. Aerosol-producing devices that have been associated with outbreaks include cooling towers, evaporative condensers, respiratory therapy equipment, showers and faucets, whirlpool spas, decorative fountains, and an ultrasonic mist machine in a supermarket. While it has historically been believed that M. pneumoniae primarily involves adolescents or young adults, recent studies suggest that this organism causes pneumonia among healthy adults of any age [30]. In the Ohio Community Based Pneumonia Incidence Study, this pathogen was an important cause of CAP both in persons under 50 years of age as well as in older age groups [5]. M. pneumoniae infections are ubiquitous and occur in both urban and rural settings. In urban areas, infection tends to be endemic, usually occurring year round; and epidemics often occur in cyclical 4-to 7-year intervals. Risk factors such as smoking or the presence of comorbid conditions are not as signiﬁcant for M. pneumoniae as for other respiratory pathogens. Geographic and Epidemiological Associations The prevalence of pneumonia due to speciﬁc pathogens would be expected to vary along diﬀerences in environmental conditions and other predisposing conditions. The geographic and epidemiological associations that likely inﬂuence causes of CAP may explain diﬀerences in prevalence rates for speciﬁc pathogens observed in studies from diﬀerent locations. Pathogens of geographic association include Legionella, sin nombre virus, endemic fungi, Coxiella burnetii, Francisella tularensis, and tuberculosis. Epidemiological

Note. COPD = chronic obstructive pulmonary disease. a Agent of Q fever. Source: Ref. 1.

Suspected large-volume aspiration Structural disease of the lung (bronchiectasis or cystic fibrosis) Injection drug use Airway obstruction

Poor dental hygiene Epidemic Legionnaire’s disease Exposure to bats or soil enriched with bird droppings Exposure to bird Exposure to rabbits HIV infection (early stage) Travel to the Southwestern United States Exposure to farm animals or parturient cats Influenza active in community

Nursing-home residency

Alcoholism COPD/smoker

Condition

Streptococcus pneumoniae, anaerobes, gram-negative bacilli S. pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Legionella species S. pneumoniae, gram-negative bacilli, H. influenzae, Staphylococcus aureus, anaerobes, Chlamydia pneumoniae Anaerobes Legionella species Histoplasma capsulatum Chlamydia psittaci Francisella tularensis S. pneumoniae, H. influenzae, Mycobacterium tuberculosis Coccidioides immitis Coxiella burnetii a Influenza, S. pneumoniae, S. aureus, Streptococcus pyogenes, H. influenzae Anaerobes, chemical pneumonitis Pseudomonas aeruginosa, Burkholderia (Pseudomonas) cepacia, or S. aureus S. aureus, anaerobes, M. tuberculosis Anaerobes

Commonly encountered pathogens

TABLE 4 Epidemiological and Underlying Conditions Related to Speciﬁc Pathogens in Selected Patients with CommunityAcquired Pneumonia

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conditions associated with speciﬁc pathogens in selected patients with CAP are listed in Table 4. Etiology Correlated with Site of Care An awareness of the likely etiology and diﬀerent settings is important for the appropriate formulation of guidelines relevant to CAP patients. Thus, there is practical importance in characterizing the etiology of CAP based on the severity of disease as judged by the site of care (outpatient vs. inpatient vs. ICU admission). Table 5 lists the most common pathogens associated with CAP based on the collective results of recent studies and based on relative severity of illness. In several studies that evaluated the etiology of CAP in ambulatory patients, the percent of cases due to M. pneumoniae ranged from 17 to 37% [26]. The cause of CAP treated in an ambulatory setting was evaluated by Marrie et al., who found that nearly half of the cases were due to atypical agents. The study population consisted of patients presenting to an emergency department or to practitioner oﬃces. An etiologic diagnosis was made in 50% of 149 patients using serologic methods. Sputum culture was not part of the routine protocol, which in part accounts for the ﬁnding of only one case of S. pneumoniae [31]. Etiologic agents included M. pneumoniae (22.8%), C. pneumoniae (10.7%), M. pneumoniae combined with C. pneumoniae (3.4%), and Coxiella burnetii (2.7%). The cause of the pneumonia was undetermined in 48.3%. The outcome of patients was similar, whether they had an atypical agent identiﬁed or the cause was unknown. A study of 170 patients with CAP treated as outpatients from a single center in Switzerland

TABLE 5

Etiology of Community-Acquired Pneumonia

Most Common Causesa Ambulatory patients S. pneumoniae M. pneumoniae H. influenzae C. pneumoniae Viruses

Hospitalized (Non-ICU)b

Severe (ICU)

S. pneumoniae M. pneumoniae C. pneumoniae H. influenzae Legionella spp. Aspiration

S. pneumoniae H. influenzae Legionella spp. Gram-negative bacilli S. aureus

ICU = Intensive care unit. a Based on collective data from recent studies. b Excluding Pneumocystis spp. Source: Ref. 31.

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TABLE 6 Etiology of Nonsevere Community-Acquired Pneumonia: Correlation with Severity Percentage of Cases by Fine Score

Conventional organisms S. pneumoniae H. influenzae O Atypical organisms M. pneumoniae C. pneumoniae Legionella spp Coxiella burnetti

Fine I(58)

Fine II(47)

Fine III(70)

31 28 3 0 69 40 14 0 14

55 45 4 4 45 15 9 9 11

51 46 1 3 49 14 23 4 6

( ) = number of patients. Source: Ref. 33. Fine Class-refer to Ref. 18.

found 14% and 6% of cases, respectively, with M. pneumoniae and C. pneumoniae as the likely pathogen (21.8% were attributed to S. pneumoniae) [32]. Another study evaluating patients with nonsevere CAP (mostly ambulatory) from Spain found the most commonly identiﬁed organism in patients younger than 50 years of age and without signiﬁcant comorbid conditions or abnormality of vital signs (Fine class I) was Mycoplasma (40% of cases), whereas S. pneumoniae was the most common pathogen in the older patients or those with underlying disease or abnormality of vital signs (Fine class II and III), Table 6 [33].

MICROBIOLOGICAL DIAGNOSIS The utility of diagnostic studies to determine the etiologic agents of CAP is controversial. There should be a balance between reasonable diagnostic procedures and empirical therapy. At present, there are no rapid, easily performed, accurate, cost-eﬀective methods that allow immediate results at the point of service (i.e., the initial evaluation by a clinician in an oﬃce or acute care setting). There is no routine diagnostic test that can consistently identify the etiologic agent. The recent guidelines for the management of CAP from the American Thoracic Society (ATS) advocate an empirical approach, whereas those from the Infectious Disease Society of America (IDSA) places a

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somewhat increased emphasis on diagnostic testing for the possibility of pathogen-directed antimicrobial therapy when the pathogen is identiﬁed [1,12]. The IDSA rationale is summarized as follows: To permit optimal antibiotic selection in terms of activity against a speciﬁc pathogen (this especially applies to drug-resistant S. pneumoniae); To permit antibiotic selection that limits the consequences of antibiotic abuse in terms of cost, resistance, and adverse drug eﬀects; To identify pathogens of potential epidemiological signiﬁcance such as Legionella, TB Nevertheless, it is recognized that most patients are treated empirically, especially outpatients for whom little diagnostic testing is utilized or recommended. Although no studies have clearly demonstrated a cost-eﬀective advantage of establishing an etiologic diagnosis, there really have been no speciﬁc studies designed to address this issue. An obvious concern regarding empirical therapy without pathogen identiﬁcation is the possible overuse of certain agents, which could lead to more resistance. Theoretically, one could be able to lessen the emergence of resistance, and therefore focus therapy, if one could identify the pathogen. A detailed history can be important in the evaluation of CAP and may be helpful in alerting one to the possibility of an etiologic diagnosis. Epidemiological clues that may lead to diagnosis considerations are listed in Table 4. For patients who are not seriously ill and do not require hospitalization, it is questionable whether any diagnostic tests are of beneﬁt. The IDSA guidelines state that it is desirable, but optional, to perform a sputum gram stain with or without culture; the Canadian statement suggests that sputum examination possibly could be helpful in settings where pneumococcal resistance is common; the ATS statement indicates that sputum culture and gram stain for outpatients are not required unless a drug-resistant pathogen or an organism not covered by usual empirical therapy is suspected [1,11,12]. Of all the potential diagnostic studies, the most controversial is the study of expectorated sputum for gram stain and culture. It is acknowledged that this test is limited by the fact that many patients cannot produce a good specimen, patients often receive antimicrobial agents prior to evaluation, and many specimens show inconclusive results. In addition, the results of these tests will not be available for the prescriber to direct antimicrobial therapy. Nevertheless, results of good sputum cultures may prove useful for patients who clinically fail initial treatment (i.e., if a culture reveals isolation of macrolide-resistant S. pneumoniae in a patient treated empirically with a macrolide); and such information will add to the collective data regarding the predom-

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inant strains within a local setting. (The reader is referred to more comprehensive discussions in each of the guideline statements.) However, antimicrobial therapy should be initiated promptly and should not be delayed in an attempt to obtain pretreatment specimens for microbiologic studies from acutely ill patients [it is my experience that if patients are able to produce a good sputum sample, they are able to expectorate such specimens readily. If patients are unable to produce expectorated sputum in an expeditious manner, appropriate empirical antimicrobial therapy should be initiated without delay]. MANAGEMENT Antimicrobial agents are the mainstays of treatment for patients with CAP. Decisions concerning speciﬁc therapy are guided by several considerations such as spectrum of activity, pharmacokinetics, eﬃcacy, safety proﬁle, cost, and whether a speciﬁc pathogen is identiﬁed. The emergence of resistant respiratory pathogens, particularly drugresistant strains of S. pneumoniae (DRSP), is becoming a signiﬁcant concern that has complicated initial empirical management of CAP. Despite the rapid increase in DRSP, the clinical relevance for the outcome of CAP remains controversial, depending on the class of antimicrobial agent considered. Nevertheless, awareness of this resistance has had a signiﬁcant impact on empirical therapy for patients treated for CAP because this can be a signiﬁcant disease even for those treated as outpatients. The reader is referred to Chapter 3 for further discussion of the clinical relevance of DRSP for CAP. Because patients treated for CAP in the ambulatory setting are for the most part treated empirically, the selection of speciﬁc antimicrobial regimens is based largely on the most likely pathogen. The most common (key) pathogens associated with nonsevere CAP are S. pneumoniae, M. pneumoniae, C. pneumoniae, and H. inﬂuenzae. Antimicrobial agents generally considered eﬀective for these pathogens include the macrolides, newer ﬂuoroquinolones, and doxycycline. While the h-lactam antibiotics (such as penicillins and cephalosporins) are eﬀective against most isolates of S. pneumoniae and H. inﬂuenzae, they are not clinically eﬀective for the ‘‘atypical pathogens.’’ Recent recommendations for empirical antimicrobial therapy from representative guidelines (i.e., North America and Britain) are summarized in Table 7 [1,11,12,19,34]. There is clearly a variation in health-care practices and policies in these diﬀerent geographic locations as well as in local antimicrobial susceptibilities that inﬂuence speciﬁc recommendations. Although the diﬀerent guidelines vary in their emphasis of the importance of deﬁning the etiologic agents so that directed-therapy can be implemented, it is acknowledged that the majority of patients will be treated empirically. This

Centers for Disease Control-Drug Resistant S. pneumoniae Therapeutic Working Group (2000) [34] Canadian Infectious Disease Society/Canadian Thoracic Society (2000) [11]

Guideline

Macrolideb; or doxycycline; or beta-lactamc or antipneumococcal fluoroquinoloned [Not 1st-line because of concerns for emerging resistance] Without modifying factors 1. Macrolide 2. Doxycycline With modifying factors COLDe (no recent Antibiotics or steroids) 1. New Macrolidef 2. Doxycycline COLDe (Recent Antibiotics or steroids) 1. Antipneum fluoroquind 2. [Amox/Clav or 2-G Ceph] and Macrolide

Empiric therapy for outpatientsa

TABLE 7 Comparison of Recommendations of Recently Published Guidelines for Empirical Antimicrobial Therapy of Community-Acquired Pneumonia in Adults (from North America and United Kingdom)

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Doxycycline; or macrolide; or antipneum Fluoroquind Selection considerations: choice should be influenced by regional antibiotic susceptibility patterns for S. pneumoniae and the presence of risk factors for PRSPg. For older patients or those with underlying disease, antipneum fluoroquin may be preferred; some authorities prefer to reserve fluoroquin for such patients No cardiopulmonary disease, no modifying factorsb: azithromycin or clarithromyicn (doxycycline if allergic or intolerant to macrolides) Modifying factorsh. h-lactam (cefpodoxime, cefuroxime, high-dose amoxicillin, amoxicillin/clavulanate; or parenteral ceftriaxone followed by p.o. cefpodxoime) plus [Macrolide or doxycycline]; or antipneum fluoroquind Amoxicillin 500–1000 mg t.i.d. (Alternative—erythromycin or clarithromycin)

b

Site of care. Erythromycin, clarithromycin, or azithromycin. c Cefuroxime axetil, amoxicillin, amoxicillin-clavulane, cefpodoxime, cefprozil; does not cover atypical pathogens. d Antipneumococcal fluoroquionlone=levofloxacin, sparfloxacin, gatifloxacin, moxifloxacin. e Chronic obstructive lung disease. f Clarithromycin, azithromycin. g PRSP=penicillin-resistant S. pneumoniae. h Risks for drug-resistant S. pneumoniae (includes antimicrobial therapy within past 3 months, recent hospitalization, multiple comorbidities, elderly, exposure to day-care center) or cardiopulmonary disease.

a

British Thoracic Society (2001) [19]

American Thoracic Society (2001) [12]

Infectious Diseases Society of America (2000) [1]

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is particularly the case for outpatients for whom diagnostic testing is not cost eﬃcient and is not emphasized. Moreover, even at tertiary-level university centers where multiple diagnostic testing methods are used for patients who require hospitalization, an etiologic agent is found in only 50% (approximately) of cases [27]. The selection of speciﬁc antimicrobial regimens for empirical therapy in the guidelines is based largely on the most likely pathogens (aided by knowledge of commonly encountered pathogens in one’s own geographic area and an appreciation of their usual susceptibilities patterns), and clinical studies. Other factors for consideration of speciﬁc antimicrobials that are mentioned in some of the guidelines include tolerance (adverse eﬀects), ease of administration, and cost. Epidemiological information that may indicate the likelihood of a particular pathogen (such as recent epidemics of inﬂuenza, recent travel, and recent exposure to animals or other patients with speciﬁc infections) and disease severity (i.e., outpatient vs. inpatient) also signiﬁcantly inﬂuences therapeutic choices. Recommendations from Recent Guidelines for Empirical Therapy of Outpatient CAP All the new North American guidelines variably recommend macrolides, doxycycline, or an antipneumococal ﬂuoroquinolone (i.e., levoﬂoxacin, gatiﬂoxacin, and moxiﬂoxacin) as treatment options for patients who are mildly ill and can be treated as outpatients. In general, the North American guidelines recommend a macrolide as ﬁrst-line treatment for outpatients with no comorbidity or risk factors for DRSP. In the Canadian statement, outpatients are stratiﬁed into those without modifying factors, for whom a macrolide may be used, and those with modifying factors (such as chronic obstructive lung disease or use of recent antibiotics or steroids—for which there may be a greater likelihood of DRSP) for whom ﬂuoroquinolones are considered more appropriate as ﬁrst-line empirical therapy. The IDSA statement indicates that the selection considerations among the three options should be inﬂuenced by regional antibiotic susceptibility patterns for S. pneumoniae and the presence of risk factors for drug-resistant S. pneumoniae (such as the use of antimicrobial agents within the previous 3 months). The statement further indicates that ‘‘for older patients or those with underlying disease, a ﬂuoroquinolone may be a preferred choice; some authorities prefer to reserve ﬂuoroquinolones for such patients’’—thus, implying macrolide as ﬁrst-line therapy for those patients without comorbidity or risk factors for DRSP. The CDC statement is similar but stresses that macrolides should be used ﬁrst-line and ﬂuoroquinolones should be reserved for cases associated with failure to or because of allergy to

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other agents or cases due to documented DRSP. The rationale is that fear of widespread use may lead to the development of ﬂuoroquinolone resistance among the respiratory pathogens (as well as other pathogens colonizing the treated patients). Similar to the Canadian statement, the revised ATS guidelines recommends stratifying outpatients into two categories (Table 7) with macrolides being recommended as ﬁrst-line therapy for patients with no cardiopulmonary disease, and no risks for DRSP, aspiration, or enteric gramnegatives. Doxycycline is a second choice (because of less reliable activity against S. pneumoniae) if patients are intolerant of or allergic to macrolides. The statement indicates that if H. inﬂuenzae is not likely, any macrolide could be used, including erythromycin. For more complex outpatients, the ATS statement recommends either a h-lactam/macrolide combination or monotherapy with an antipneumococcal ﬂuoroquinolone. The rationale is the concern for likely DRSP and the possibility of clinical failure if the macrolides are used alone. One diﬀerence between the North American guidelines and the British Thoracic Society (BTS) guidelines is the positioning of the macrolides as ﬁrstline options for empirical therapy of ‘‘low-risk’’ outpatients. All the North American statements include the macrolides as preferred ﬁrst-line or as an equal option for patients with low risk for drug-resistant strains, whereas the primary agent recommended in the BTS statement is h-lactam (i.e., amoxicillin) and not macrolides (the macrolides are positioned as alternative agents). The diﬀerence in the emphasis placed on the importance of the ‘‘atypical’’ pathogens as well as the expression of macrolide-resistant S. pneumoniae in North America compared with Europe partly explains this variance. Because M. pneumoniae and C. pneumoniae are common causes of outpatient CAP (including older patients) and it is not possible to reliably predict the etiology solely on clinical manifestations, the North American statements include coverage of these common pathogens for empirical therapy. On the other hand, the British guidelines state that because M. pneumoniae exhibits epidemic periodicity every 4–5 years and largely aﬀects younger persons, a policy for initial empirical therapy that aims always to cover this pathogen is unnecessary. Furthermore, in the United States most macrolide resistance is a result of increased drug eﬄux encoded by mef gene and with MICs < 16 mg/ml. It is possible that achievable levels of the newer macrolides (azithromycin, clarithromycin) may overcome this resistance. In Europe, most macrolide resistance is caused by ribosomal methylase encoded by erm gene; this results in high-level resistance to macrolides that cannot be overcome. In addition, at the time of the development of the North American guidelines, cases of macrolide failure for outpatients, particularly for cases not associated with risks for DRSP, had been infrequent. Of note, however, the continuing increasing frequency of macrolide resistance among pneumo-

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cocci in North America is of concern and will require treatment recommendations for empirical therapy of CAP in the United States to be periodically reevaluated. New Drugs While managing CAP according to the empirical principles outlined before has led to measurable beneﬁts in patient outcomes, the morbidity and mortality associated with this disease remain generally unchanged over the past few decades. This is due, in part, to the increasing prevalence of patients at risk (i.e., elderly, increased underlying conditions) as well as the limitations of current antibiotics in the face of growing antibacterial resistance. These issues highlight the need for antibacterial agents with activity against resistant strains of S. pneumoniae as well as with a low potential to induce resistance. Until recently, therapeutic options for managing CAP due to known or suspected cases of drug-resistant pneumococcal infections were primarily limited to the ﬂuoroquinolones. Although vancomycin is nearly certain to provide antibiotic coverage for DRSP, it is not active against other key respiratory pathogens (i.e., atypicals, H. inﬂuenzae) and there is a strong reason not to use this drug until it is needed because of fear of emergence of other resistant organisms (i.e., VRE, VRSA). Other agents eﬀective against DRSP include quinupristin/dalfopristin, linezolid and the ketolides. However, the focus of therapy of quinupristin/dalfopristin and linezolid is more for nosocomial infections (and particularly for VRE or MRSA). Telithromycin is the ﬁrst of a new class of macrolide-type antibiotic, the ketolides [35]. It is a novel addition to the macrolide–lincosamide–streptogramin-B (MLSB) group of antibacterials speciﬁcally designed to treat communityacquired RTIs. In vitro studies have demonstrated the eﬃcacy of telithromycin against such common respiratory pathogens as S. pneumoniae (including penicillin- and erythromycin-resistant strains), H. inﬂuenzae, M. catarrhalis, Streptococcus pyogenes, and S. aureus and against Legionella, Chlamydia, and Mycoplasma species. Furthermore, its structure confers a low potential to select for resistance or induce cross-resistance among other MLSB antibacterials. Length and Route of Antimicrobial Treatment There is a lack of controlled trials that can speciﬁcally address the question as to length of therapy. The decision is usually based on the pathogen isolated, response to treatment, comorbid illness, and complications. Until further data are forthcoming, it seems reasonable to treat bacterial infections such as those caused by S. pneumoniae until a patient is afebrile for 72 hours. Most randomized clinical trials for the new ﬂuoroquinolones or newer macrolides

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have shown good outcomes with 7–10 days of therapy (azithromycin may be used for shorter courses of treatment in ambulatory patients because of its longer half-life in tissue). Pneumonia caused by Legionella should be treated longer (i.e., 14–21 days), depending on the clinical response. For many pathogens, there is no clear advantage of intravenous therapy over oral therapy, and the panel endorses use of oral antimicrobial agents for patients who tolerate these drugs if oral bioavailability and activity are adequate. However, for most patients admitted to the hospital, the common practice is to at least begin therapy with intravenous drugs. Changing from intravenous to oral therapy is associated with a number of economic, health care, and social beneﬁts. Conditions for changing from intravenous to oral include stable or improving condition, ability to ingest drugs, and a functional gastrointestinal tract. In most cases these conditions are met within 2–3 days. Ideally the parenteral drugs should be given in an oral formulation with adequate bioavailability; if no oral formulation is available, then an oral agent with a similar spectrum of activity should be selected on the basis of in vitro or predicted susceptibility patterns of established or probable pathogen. PREVENTION OF CAP Despite controversies over eﬃcacy of the polysaccharide pneumococcal vaccine (PPV), both PPV and the inﬂuenza vaccines are recommended according to current guidelines by the Centers for Disease Control and Prevention (at ages 65 and 50 respectively for immunocompetent adults without other risk factors) [36,37]. In a recent meta-anaylysis of 14 trials totaling more than 48,000 patients, PPV prevented deﬁnite pneumonia by 71% and mortality by 32% (but not all-cause death) [38]. However, there was no beneﬁt seen for patients 55 years of age or older. A signiﬁcant advance has been the development and licensure of the pneumococcal conjugate vaccine in infants. The beneﬁts of this vaccine over the PPV have yet to be demonstrated in adults [39]. Smoking-cessation counseling for all smokers is an important eﬀort for reduction of the burden of all respiratory tract infections. CONCLUSION Timeliness and appropriateness of antimicrobial therapy constitute the hallmarks of CAP treatment. The mortality rate is relatively low in the mild to moderate cases (Classes I through III). These patients may be treated in the ambulatory setting. CAP will continue to represent a signiﬁcant threat to patients in the future as the number of patients at risk (the elderly and those with comorbid conditions) increase. Better, rapid diagnostic methods to

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deﬁne the etiologic pathogens are needed to allow more speciﬁc, directed therapy. It seems reasonable that patients will respond better and antibiotics can be used more appropriately if the speciﬁc pathogen is known, but good studies in support of this approach are needed. Although not discussed in this review, a greater understanding of the pathogenesis and host response should lead to new approaches of therapy. As the complexities of the host response are revealed, it is likely therapeutic beneﬁts may be realized. The optimal approach to management continually will need to be reassessed as new information is generated.

REFERENCES 1. Bartlett JG, Dowell SF, Mandell LA, File TM Jr, Musher DM, Fine MJ. Guidelines from the Infectious Diseases Society of America. Practice guidelines for the management of community-acquired pneumonia in adults. Clin Infect Dis 2000; 31:347–382. 2. Mandell LA. Community-acquired pneumonia: etiology, epidemiology, and treatment. Chest 1995; 108(suppl):35S–42S. 3. Foy HM, Cooney MK, Allan I, et al. Rates of pneumonia during inﬂuenza epidemics in Seattle, 1964 to 1975. JAMA 1979; 241:253. 4. Houston MS, Silverstein MD, Suman VJ. Community-acquired lower respiratory tract infection in the elderly: A community-based study of incidence and outcome. J Am Board Fam Pract 1995; 8(5):347–356. 5. Marston BJ, Plouffe JF, File TM Jr, and the CBPIS Study Group. Incidence of community-acquired pneumonia requiring hospitalization: Results of a population-based active surveillance study in Ohio. Arch Intern Med 1997; 157: 1709–1718. 6. European Study on Community-Acquired Pneumonia (ESOCAP) committee, Huchon G, Woodhead M, et al. Management of adult community-acquired lower respiratory tract infections. Eur Respir Rev 1998; 8(61):391–426. 7. Marrie TJ. Community-acquired pneumonia: epidemiology, etiology, treatment. Infect Dis Clin North Am 1998; 12(3):723–739. 8. Koivula I, Sten M, Makela PH. Risk factors for pneumonia in the elderly. Am J Med 1994; 96:313–320. 9. Saitz R, Ghali WA, Moskowitz MA. The impact of alcohol-related diagnoses on pneumonia outcomes. Arch Intern Med 1997; 157:1446–1452. 10. Fine MJ, Smith MA, Carson CA, et al. Prognosis and outcomes of patients with community-acquired pneumonia. JAMA 1996; 275:134–141. 11. Mandell LA, Marrie TJ, Grossman RE, et al. Canadian guidelines for the initial management of community-acquired pneumonia: an evidence-based update by the Canadian Infectious Diseases Society and the Canadian Thoracic Society. Clin Infect Dis 2000; 31:383–421. 12. Niederman MS, Mandell LA, Anzueto A, et al. Guidelines for the management

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of adults with community-acquired pneumonia (American Thoracic Society). Am J Respir Crit Care Med 2001; 163:1730–1754. Metlay JP, Kapoor WN, Fine MJ. Does this patient have community-acquired pneumonia? JAMA 1997; 278:1440–1445. Metlay JP, Atlas SJ, Borowsky LH, Singer DE. Time course of symptom resolution in patients with community-acquired pneumonia. Resp Med 1998; 92: 1137–1142. Fine MJ, Stone RA, Singer DE, et al. Processes and outcomes of care for patients with community-acquired pneumonia: results from the Pneumonia Patient Outcomes Research Team (PORT) cohort study. Arch Intern Med 1999; 159:970– 980. Niederman MS, McCombs JS, Unger AN, Kumar A, Popovian R. The cost of treating community-acquired pneumonia. Clin Ther 1998; 20:820–837. Coley CM, Yi-Hwei L, Medsger AR, et al. Preference for home vs. hospital care among low-risk patients with community-acquired pneumonia. Arch Intern Med 1996; 156:1565–1571. Fine MJ, Auble TE, Yealy DM, et al. A prediction rule to identify low-risk patients with community-acquired pneumonia. N Engl J Med 1997; 336:243– 250. British Thoracic Society. Guidelines for the management of community-acquired pneumonia in adults. Thorax 2001; 56(suppl IV):iv1–iv64. Atlas SJ, Benzer TI, Borowsky LH, et al. Safely increasing the proportion of patients with community-acquired pneumonia treated as outpatients: an interventional trial. Arch Intern Med 1998; 158:1350–1356. Flanders WD, Tuckter G, Krishnadasan A, Martin D, Honig E, McClellan WM. Validation of the pneumonia severity index. Importance of study-speciﬁc recalibration. J Gen Intern Med 1999; 14:333–340. Marras TK, Gutierrez C, Chan CK. Applying a prediction rule to identify lowrisk patients with community-acquired pneumonia. Chest 2000; 118:1339–1343. Chan SS, Yuen EH, Kew J, Cheung WL, Cocks RA. Community-acquired pneumonia—implementation of a prediction rule to guide selection of patients for outpatient treatment. Eur J Emerg Med 2001; 8:279–286. Stauble SP, Reichlin S, Dieterle T, Leimenstoll B, Schoenenberger R, Martina B. Community-acquired pneumonia—which patients are hospitalized? Swiss Med Weekly 2001; 131:188–192. Lim WS, Lewis S, MacFarlane JT. Severity prediction rules in communityacquired pneumonia: a validation study. Thorax 2000; 55:219–223. File TM Jr, Tan JS. Incidence, etiologic pathogens and diagnostic testing of community-acquired pneumonia. Current Opinion Pulm Med 1997; 3:89–97. Bartlett JG, Mundy LM. Current concepts: Community-acquired pneumonia. N Engl J Med 1995; 333(24):1618–1624. File TM Jr, Plouﬀe JF. Legionella. Curr Infect Dis Reports 1999; 1:65–72. Straus WL, Plouﬀe JF, File TM Jr, et al. Risk factors for domestic acquisition of Legionnaires’ disease. Arch Intern Med 1996; 156:1685–1692. File TM Jr, Tan JS, Plouﬀe JF. The role of atypical pathogens: Mycoplasma

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14 Treatment of Hospitalized Patients with Community-Acquired Pneumonia Michael S. Niederman Winthrop University Hospital Mineola and SUNY at Stony Brook Stony Brook, New York, U.S.A.

Pneumonia is the sixth leading cause of death in the United States and the number-one cause of death from infectious diseases [1]. The infection can occur in patients who are living in the community (community-acquired pneumonia, CAP) or in those who are already hospitalized (nosocomial pneumonia, NP), but today the distinction between community and nosocomial infection is less clear because the ‘‘community’’ includes complex patients such as those who have recently been hospitalized, those in nursing homes, and those with chronic diseases who are commonly managed in such facilities as dialysis centers or nursing homes. Although patients with varying degrees of immune function can be aﬀected by CAP, this discussion is conﬁned to patients with CAP admitted to the hospital who are immune competent individuals, and excludes discussion of patients with HIV infection or traditional immune suppression (cancer chemotherapy, immune suppressive medications). Of the 5.6 million patients with CAP treated in 1994, only 1.1 million were admitted to the hospital, yet this minority of patients accounted for the majority of cost in managing this illness [2]. In fact, a total of $8.4 billion was 279

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spent on the care of CAP patients, and only $0.4 billion was spent on the care of the 4.5 million outpatients [2]. Among those who are hospitalized, the elderly account for a disproportionate amount of expense: they make up only about a third of all pneumonia patients, yet are responsible for more than half of the dollars spent on this illness. This in turn is a reﬂection of the fact that the elderly are more often hospitalized than a younger population and have a higher frequency of comorbid illness [2]. From these data, it is clear that one of the major management issues in CAP is deciding who gets admitted to the hospital. In addition, once patients are hospitalized, the key management decisions hinge on deciding the appropriate site of care (medical ﬂoor or ICU), initiating the correct therapy as soon as possible, and recognizing the patient’s response to therapy. If a patient responds appropriately, then the hospital stay can be abbreviated, especially with a timely switch to oral antibiotic therapy. If the patient is not responding as expected, then it is necessary to do a thorough evaluation to recognize unusual or unexpected pathogens (tuberculosis, fungal disease), to treat drug-resistant organisms, to diagnose pneumonia complications (empyema, pulmonary embolus), and to rule out mimics of pneumonia (malignancy, inﬂammatory lung disease). This chapter focuses on the management of inpatients with CAP and emphasizes the approach to management, including algorithms for therapy and the management of this illness in an era of increasingly common rates of infection with antibiotic-resistant organisms.

CLINICAL FEATURES OF CAP Symptoms (Table 1) The classic symptoms of CAP, including cough, sputum production, dyspnea, and fever, are common in patients with an intact immune response, but less frequent in the elderly and chronically ill. Although cough is present in up to 80% of all patients, it is less frequent in those who are elderly, in those with serious comorbidity, or in individuals coming from nursing homes [3,4]. Elderly patients with CAP may have nonrespiratory presentations of illness and may be afebrile, and these ﬁndings have been identiﬁed as predictors of mortality [5]. This may be the consequence of the fact that a nonrespiratory presentation is usually a reﬂection of an impaired immune response, but it may also be a reason for the patient to have a delayed presentation to medical attention, and the physician in turn may delay the diagnosis of pneumonia in this setting. In keeping with these observations, the absence of pleuritic chest pain, which is generally a common symptom in patients with certain forms of pneumonia, was identiﬁed in one study to be a poor prognostic ﬁnding [6]. In an elderly patient, the nonrespiratory presentations of CAP can include symptoms of confusion, falling, failure to thrive, altered functional

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281

Clinical Features of CAP

Finding Fever, chills

Dyspnea Worsening of chronic underlying illness Cough and purulent sputum

Duration of symptoms Absence of respiratory symptoms

Impaired consciousness, poor swallowing Nonrespiratory symptoms: falling, confusion, decreased functional status Respiratory rate

Bronchial breath sounds, egophony, dullness, reduced breath sounds, crackles Skin rash

Elevated liver function tests

Comment More likely with intact immune system, but can be absent in the elderly and immune suppressed (including steroid therapy) Present in only 70% May be the only clue to pneumonia in the elderly Cough in up to 80%; 50% with purulence. Appearance of sputum cannot always identify bacterial infection. Tend to be longer in the elderly Associated with increased mortality, especially the absence of pleuritic chest pain Aspiration risk factors; consider in patients with recurrent infection May be the only symptoms related to pneumonia in the elderly Rarely <20 if pneumonia, and mortality risk is increased if >30/min. Must be counted on admission for all patients. Suggests pneumonia and should prompt a chest radiograph S. aureus, P. aeruginosa, Mycobacterium tuberculosis, Endemic fungi, Aspergillus, Varicella- zoster, herpes simplex, M. pneumoniae S. pneumoniae, S. aureus, P. aeruginosa, M. tuberculosis, Legionella, H. influenzae, Coccidioides immitis, Aspergillus, Herpes simplex, varicella -zoster, Q fever, M. pneumoniae, C. psittaci

capacity, or deterioration in a preexisting medical illness, such as congestive heart failure or dementia [3,4,5,7]. In one study, delirium or acute confusion were signiﬁcantly more frequent in the elderly patients with pneumonia than in age-matched controls who did not have pneumonia [7]. In that study, there was no association between the etiologic pathogen and the symptoms of pneumonia, except for pleuritic chest pain, which was more common when Streptocococcus pneumoniae was the pathogen. Elderly patients are more

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commonly malnourished than other CAP patients (16% vs. 47% of controls), with kwashiorkor-like malnutrition being the predominant type of nutritional defect and one associated with delirium on initial presentation [7]. Several studies have documented a substantially higher mortality rate in the elderly than in other individuals with CAP and thus it is not surprising that in one study of 1812 patients of all ages, older patients tended to have a longer duration of symptoms, such as cough, sputum production, dyspnea, fatigue, anorexia, myalgia and abdominal pain, than did younger ones [3]. Physical Findings Physical ﬁndings of pneumonia are not speciﬁc, but include tachycardia, tachypnea, crackles, rhonchi and signs of pulmonary consolidation (egophony, bronchial breath sounds, dullness to percussion). Patients may also have signs of pleural eﬀusion. In some patients, the presence of extrapulmonary ﬁndings can help to diagnose metastatic infection (arthritis, endocarditis, meningitis), or add to the suspicion of an ‘‘atypical’’ pathogen such as M. pneumoniae or C. pneumoniae, the former of which can be accompanied by bullous myringitis, skin rash, pericarditis, hepatitis, hemolytic anemia, or meningoencephalitis. Measurement of respiratory rate is a key diagnostic and prognostic maneuver. For example, in elderly patients an elevation of respiratory rate can be the initial presenting sign of pneumonia, preceding other clinical ﬁndings by as much as 1–2 days. In a prospective study in a long term care setting, 19 of 21 patients who were diagnosed with lower respiratory tract infection had a respiratory rate above the normal range of 16–25, and in general the elevated rate preceded other clinical ﬁndings [8]. In another study, tachypnea was present in over 80% of all CAP patients, being present more often in the elderly than in younger patients with pneumonia [3]. Measurement of respiratory rate also is of prognostic signiﬁcance, and the ﬁnding of a respiratory rate of more than 30 per minute is one of several factors associated with increased mortality [1]. Radiographic Features Although most studies of CAP require the presence of a new radiographic inﬁltrate, not all patients will have this ﬁnding when ﬁrst evaluated. Even when the radiograph is negative, if the patient has appropriate symptoms and focal physical ﬁndings, pneumonia may still be present. In one study, 47 patients with clinical signs and symptoms of CAP were evaluated with both a chest radiograph and a high-resolution CT scan of the chest and there were eight patients identiﬁed by CT scan as having pneumonia who had a negative chest radiograph. In many instances, there were more extensive abnormalities found on CT scan, with 16 patients shown to have bilateral inﬁltrates by this

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technique, compared to only 6 with this ﬁnding on chest radiograph [9]. Bronchopneumonia was the most common abnormality deﬁned by either technique. The ﬁndings of this study conﬁrm the need to repeat the chest ﬁlm after 24–48 hours in certain symptomatic patients with an initially negative chest ﬁlm. The reason for an initially negative chest ﬁlm is not clear, but some studies have suggested that febrile and dehydrated patients can have a normal ﬁlm when ﬁrst admitted with pneumonia, but it is still uncertain if it is possible to ‘‘hydrate a pneumonia’’ after admission to the hospital [10]. In COPD patients, an exacerbation can be accompanied by the presence of an inﬁltrate (CAP), or without a radiographic abnormality (acute bronchitic exacerbation). One recent study has shown that if a radiographic abnormality is present, then the illness is more severe, and the complications greater, than if no inﬁltrate is present [11]. It is generally not possible to deﬁne the etiology of CAP on the basis of speciﬁc radiogaphic ﬁndings; however, there are certain patterns that have been associated with speciﬁc pathogens [10]. Focal consolidation can be seen with infections caused by pneumococcus, Klebsiella, aspiration (especially if in the lower lobes or other dependent segments), S. aureus, L. pneumophila, H. inﬂuenzae, M. pneumoniae, and C. pneumoniae. Interstitial inﬁltrates are present in patients with viral pneumonia as well as infection due to M. pneumoniae, C. pneumoniae, C. psittaci, and P. carinii. Lymphadenopathy with an interstitial pattern should raise concerns about anthrax, Francisella tularensis and C. psittaci; adenopathy can be seen with focal inﬁltrates in tuberculosis, fungal pneumonia, and bacterial pneumonia. Cavitation can be the result of an aspiration lung abscess, or infection with S. aureus, aerobic gram-negatives (including P. aeruginosa), tuberculosis, fungal infection, nocardia and actinomycosis. Pleural eﬀusion may be present, and it is necessary to sample the pleural ﬂuid in order to distinguish empyema from a simple parapneumonic eﬀusion. In some studies, the presence of bilateral pleural eﬀusion was an independent predictor of short-term mortality in CAP [12]. Pneumococcal pneumonia is the infection most commonly complicated by eﬀusion (36–57% of patients), but other pathogens causing eﬀusion include H. inﬂuenzae, M. pneumoniae, Legionella, anthrax, tularemia and tuberculosis [13,14]. Typical vs. Atypical Pneumonia Syndromes Using clinical patterns of pneumonia symptoms and ﬁndings to deﬁne the etiology of CAP is generally not helpful, and separating features into either ‘‘typical’’ or ‘‘atypical’’ pneumonia is of historic interest but cannot directly aid patient management. The typical pneumonia syndrome is characterized by sudden onset of high fever, shaking chills, pleuritic chest pain, lobar

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consolidation, a toxic-appearing patient, and the production of purulent sputum. Although this pattern has been attributed to pneumococcus and other bacterial pathogens, these organisms do not always lead to such classic symptoms. The atypical pneumonia syndrome, which is characterized by a subacute illness, nonproductive cough, headache, diarrhea, or other systemic complaints, is usually the result of infection with Mycoplasma pneumoniae, C. pneumoniae, Legionella sp., or viruses. However, patients with impaired immune responses (especially the elderly with chronic illness) may present in this fashion, even when bacterial pneumonia is present, and thus it is usually not possible to use the features on clinical presentation to predict the likely etiologic agent [1,15–18]. In fact, in one study the clinical features were no more than 42% accurate in diﬀerentiating pneumococcus, Mycoplasma pneumoniae, and other pathogens from one another [16].

ETIOLOGIC PATHOGENS Diagnostic testing has limited value in patients with CAP, and can deﬁne an etiologic agent in only about half of all patients, raising the possibility that we do not know all the organisms that can cause CAP [1,17]. In the past three decades, a variety of new pathogens for this illness have been identiﬁed, including Legionella pneumophila, Chlamydia pneumoniae, and hantavirus. In addition, antibiotic-resistant variants of common pathogens such as Streptococcus pneumoniae and H. inﬂuenzae have become increasingly common. In an era where bioterrorism remains a threat, it is important to consider such organisms as Bacillus anthracis, Yersinia pestis, and Francisella tularensis in patients who present with a syndrome of CAP. Streptococus pneumoniae The most common pathogen for CAP in any patient population is S. pneumoniae, and this organism may even be responsible for many episodes of inpatient CAP that go undiagnosed by standard testing. In one study using transthoracic needle aspirates in patients with no organisms recovered by conventional diagnostic testing, half of the patients in whom the needle provided a diagnosis had pneumococcus identiﬁed as the pathogen [19]. Pneumococcal infection is more common in the elderly; those with asplenia, multiple myeloma, congestive heart failure, alcoholism; after inﬂuenza; and in patients with chronic lung disease. In patients with HIV infection, pneumococcal pneumonia with bacteremia is more common than in healthy populations of the same age. The classic radiographic pattern is a lobar consolidation, but bronchopneumonia can also occur, and in some series, this is the most common pattern [20]. Bacteremia is present in up to 20% of

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hospitalized patients with this infection, but the impact of this ﬁnding on mortality is uncertain [21]. Extrapulmonary complications include meningitis, empyema, arthritis, endocarditis, and brain abscess. In the past decade, antibiotic resistance among pneumococci has become increasingly common, and penicillin resistance, along with resistance to other common antibiotics (macrolides, trimethoprim/sulfamethoxizole, selected cephalosporins), is present in over 40% of these organisms [1,22]. Because most penicillin resistance is of the ‘‘intermediate’’ type (penicillin minimum inhibitory concentration, or MIC, of 0.1 to 1.0 mg/L) and not of the high-level type (penicillin MIC of 2.0 or more), the clinical signiﬁcance of these organisms is uncertain. Although not all resistance is likely to be relevant, experts believe that CAP with organisms having a penicillin minimum inhibitory concentration (MIC) of z 4 mg/L can lead to an increased risk of death [1,14,21,23]. Although Pallares et al. were unable to show an impact of resistance (penicillin MIC > 0.12 mg/L) on mortality, after adjusting for severity of illness in a population of 504 infected patients, Turrett and colleagues found that high-level resistance was a predictor of mortality in a population of 462 patients with pneumococcal bacteremia, of whom more than half were HIV positive [24,25]. In other studies, investigators did not ﬁnd an increased risk of death from infection with resistant organisms but did ﬁnd an enhanced likelihood of suppurative complications (empyema), and a more prolonged hospital length of stay [26,27]. While these studies involved relatively small number of patients, Feikin et al. studied the impact of pneumococcal resistance in 5837 patients with bacteremic CAP [23]. They found an increased mortality for patients with a penicillin MIC of at least 4 mg/L or greater, or with a cefotaxime MIC of 2.0 mg/L or more. However, this increased mortality was only present if patients who died in the ﬁrst 4 days of therapy were excluded from analysis. One limitation of this study was a failure to correct for severity of illness or accuracy of therapy. More recently, Moroney et al. used both cohort study and matched-control methods and found that severity of illness, and not resistance or accuracy of therapy, was the most important predictor of mortality [28]. Interestingly, in the case-control part of the study, severity of illness was greater in patients without resistant organisms, implying a loss of virulence among organisms that become resistant, a ﬁnding echoed in another study that found absence of invasive illness to be a risk factor for pneumococcal resistance [29]. Atypical Pathogens Although the term atypical should not be used to describe a speciﬁc clinical syndrome, the term can be used to refer to a group of pathogens that includes

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M. pneumoniae, C. pneumoniae, and Legionella, all organisms that must be treated with a macrolide, tetracycline, or a quinolone. Infection with these pathogens is common in patients of all ages, not just young and healthy individuals, and these organisms have even been reported among the elderly in nursing homes [1,30,31]. In addition, they can occur as either primary pathogens or may be part of a mixed infection, along with traditional bacterial pathogens. When mixed infection is present, it may lead to a more complex course and a longer length of stay than if a single pathogen is present. There may be a particular synergy between C. pneumoniae and pneumococcus, with either sequential or mixed infection with C. pneumoniae leading to a more severe course for pneumococcus [32]. The frequency of atypical pathogens can be as high as 60% in some series, with as many as 40% of all CAP patients having mixed infection [33]. Although the exact frequency of infection with these organisms is uncertain, their importance has been suggested in studies of inpatients, which have shown a reduced mortality and length of stay when patients received empiric therapy that accounted for these organisms, compared to regimens that do not account for these organisms [34,35]. Although these organisms may be important, there may be both temporal and geographic variability in their occurrence. In one study, the beneﬁt of providing empiric therapy directed at atypical pathogens was variable, being more important in some calendar years than in others [35]. The incidence of Legionella infection among admitted patients has varied from 1% to 15% or more and is also a reﬂection of geographic and seasonal variability in infection rates, as well as a reﬂection of the extent of diagnostic testing. This organism is a particular problem in patients with severe CAP, but its frequency is varable. In one report, atypical pathogens were present in almost 25% of all ICU CAP patients, but the responsible organism varied over time, with Legionella being common in one time period; but in the same hospital a decade later, it had been replaced by Mycoplasma and Chlamydia infection [36]. Although it is very diﬃcult to use clinical features to predict the microbial etiology of CAP, there are descriptions of a classic Legionella syndrome, which is characterized by high fever, chills, headache, myalgias, and leukocytosis, along with preceding diarrhea, early onset of mental confusion, hyponatremia, relative bradycardia, and liver function abnormalities. This syndrome is usually not present, and the illness can be rapidly progressive, with the patient appearing to be quite toxic, and thus this diagnosis should always be considered in all patients admitted to the ICU with CAP. Gram-Negative Bacteria The most common gram-negative organism causing CAP is H. inﬂuenzae, a common pathogen in the elderly and in those who smoke cigarettes or who

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have chronic bronchitis [1]. H. inﬂuenzae can be either a typable (encapsulated) or nontypable organism, and can lead to bronchopneumonia and, rarely, empyema. Enteric gram-negatives are generally not common in CAP, unless the patients are elderly and have chronic cardiac or pulmonary disease or are alcoholics. In these patients, organisms such as E. coli and Klebsiella pneumoniae can be found. Pseudomonas aeruginosa is an uncommon cause of CAP but can be isolated from patients with CAP and bronchiectasis, and in those with severe forms of CAP, particularly in elderly patients older than 75 [1,37]. In one recent study, enteric gram-negative bacteria were present in 11% of 559 hospitalized CAP patients, with P. aeruginosa being the dominant pathogen. Pneumonia due to these organisms was associated with a 3.4-fold increased risk of mortality. Risk factors for gram-negative infection were probable aspiration, prior antibiotic therapy, prior hospitalization, and the presence of pulmonary comorbidity. The last two factors were also risk factors for infection with P. aeruginosa [38]. In very elderly (> age 75) patients admitted to the ICU with CAP, P. aeruginosa has also been identiﬁed, particularly in nursing home residents who have bronchiectasis and impaired functional status [37]. Other Organisms CAP can also be caused by S. aureus, which can lead to severe illness and to cavitary lung infection. This organism can also seed the lung hematogenously from a vegetation in patients with right-sided endocarditis or from septic venous thrombophlebitis (from central venous catheter or jugular vein infection). The role of anaerobes in CAP in uncertain, but they may be

TABLE 2

Common Pathogens Causing Inpatient CAP

With Cardiopulmonary Disease and/or Modifying Factors S. pneumoniae (including DRSP), H. influenzae, M. pneumoniae, C. pneumoniae, mixed infection (bacteria plus atypical pathogen), enteric gram-negatives, aspiration (anaerobes), viruses, Legionella sp., others (M. tuberculosis, endemic fungi, Pneumocystic carinii ) With No Cardiopulmonary Disease or Modifying Factors All of the above, but DRSP and enteric gram-negatives are not likely Severe CAP, with No Risks for P. Aeruginosa S. pneumoniae (including DRSP), Legionella sp., H. influenzae, enteric gram-negative bacilli, S. aureus, M. pneumoniae, respiratory viruses, others (C. pneumoniae, M. tuberculosis, endemic fungi) Severe CAP, with Risks for P. Aeruginosa All of the pathogens above. plus P. aeruginosa

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important in patients with aspiration risk factors (neurologic illness, impaired swallowing, esophageal disease), and may cause lung abscess in dependent lung segments. The need to treat these organisms when they are part of a mixed infection with aerobic organisms is uncertain [1,14]. The incidence of viral pneumonia is diﬃcult to deﬁne, but during epidemic times, inﬂuenza should be considered; it can lead to a primary viral pneumonia or to secondary bacterial infection with pneumococcus, S. aureus, or H. inﬂuenzae. Finally, it important to always consider the diagnosis of tuberculosis in patients with CAP, and, in endemic areas, fungal infection with coccidiodomycosis and histoplasmosis, especially in HIV-infected persons.

TABLE 3

Clinical Associations with Speciﬁc Pathogens

Condition Alcoholism

COPD/current or former smoker Residence in nursing home

Poor dental hygiene Bat exposure Bird exposure Rabbit exposure Travel to SW USA Exposure to farm animals or parturient cats Post-influenza pneumonia Structural disease of lung (bronchiectasis, cystic fibrosis, etc.) Bioterrorism

Commonly Encountered Pathogens Streptococcus pneumoniae (including PRSP), anaerobes, gram-negative bacilli (possibly K. pneumoniae ) S. pneumoniae, H. influenzae, Moraxella catarrhalis, Legionella. Role of atypicals uncertain S. pneumoniae, gram-negative bacilli, H. influenzae, S. aureus (including methicillinresistant organisms), anaerobes, C. pneumoniae; consider M. tuberculosis. Modify considerations based on local epidemiology Anaerobes Histoplasma capsulatum Chlamydia psittaci, Cryptococcus neoformans, H. capsulatum Francisella tularensis Coccidioidomycosis; hantavirus in selected areas Coxiella burnetii (Q fever)

S. pneumoniae, S. aureus, H. influenzae P. aeruginosa, P. cepacia or S. aureus

Bacillus anthracis, Yersinia pestis, Francisella tularensis

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Predicting Pathogens for Specific Patient Populations Table 2 summarizes the common pathogens causing CAP in inpatients, both on the medical ward and in the ICU. The classiﬁcation is based on the severity of illness and the presence of clinical risk factors for speciﬁc pathogens, referred to as ‘‘modifying factors.’’ Patients with severe CAP may have a slightly diﬀerent spectrum of organisms than other patients with this illness, being commonly infected with pneumococcus, atypical pathogens, enteric gram-negatives (including P. aeruginosa), S. aureus, and H. inﬂuenzae. The modifying factors for DRSP are age greater than 65 years, h-lactam therapy within the past 3 months, alcoholism, immune suppressive illness (including therapy with corticosteroids), multiple medical comorbidities, and exposure to a child in a day-care [1,29,39]. The modifying factors for enteric gram-negatives include residence in a nursing home, underlying cardiopulmonary disease, multiple medical comorbidities, and recent antibiotic therapy. The risk factors for P. aeruginosa infection are structural lung disease (bronchiectasis), corticosteroid therapy (> 10 mg prednisone / day), broadspectrum antibiotic therapy for more than 7 days in the past month, and malnutrition [1]. Table 3 shows that certain clinical conditions are associated with speciﬁc pathogens, and these associations should be considered in all patients when obtaining a history. ASSESSMENT OF SEVERITY OF ILLNESS Hospitalization Decision Given the economic and social impact of pneumonia, the decision about site of initial care is one of the most important in disease management. Generally severity of illness should be determined in order to decide whether the patient should be hospitalized and whether ICU admission is needed. Although a number of prediction models have been developed to guide the admission decision, no rule is absolute and the decision to admit a patient should be based on social as well as medical considerations, and it remains an ‘‘art of medicine’’ determination. In general, the hospital should be used to observe patients who have multiple risk factors for a poor outcome, those who have decompensation of a chronic illness, or those who need therapies not easily administered at home (oxygen, intravenous ﬂuids, cardiac monitoring) [1]. Risk factors for a poor outcome include respiratory rate greater than 30/ minute, systolic blood pressure less than 90 mm Hg, diastolic BP less than 60 mm Hg, multilobar pneumonia, confusion, BUN greater than 19.6 mg/dl, PaO2 less than 60 mm Hg, PaCO2 greater than 50 mm Hg, respiratory or metabolic acidosis, or signs of systemic sepsis [1,40,41]. The British Thoracic Society (BTS) rule states that patients have a 9- to 21-fold increased risk of

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death if they have at least two of the following four criteria present: respiratory rate equal to or greater than 30/min, diastolic BP equal to or less than 60 mm Hg, BUN greater than 19.6 mg/dL, and confusion [41,42]. One approach to the admission decision was developed by the investigators in the Pneumonia Outcomes Research Team (PORT) study who developed a mortality prediction rule that classiﬁes all patients into one of ﬁve groups (classes I through V), each with a diﬀerent risk of death [40]. In the Infectious Disease Society of America (IDSA) guidelines for CAP, this mortality risk score, the Pneumonia Severity Index (PSI), has been used to guide the admission decision, recommending admission for patients in classes IV and V, with a predicted mortality risk of 8.2–9.3% and 27–31.1%, respectively, while outpatient care was recommended for patients in classes I and II, with a mortality risk of 0.1–0.4% and 0.6–0.7%, respectively [14]. Patients in class III had an intermediate risk of death, 0.9–2.8%, and the recommendation was that the admission decision be individualized for these patients. The scoring system is complex, and patients have points calculated based on such factors as age, sex, the presence of comorbid medical disease, certain physical ﬁndings, and certain laboratory data [40]. In prospective studies, the limitations of the PORT model have been identiﬁed, particularly the ﬁnding that as many as 30–40% of those who are admitted based on clinical judgment fall into the low-risk groups [43,44]. In one such study, 166 out of 826 patients presenting to the emergency department fell into classes I–III, and when the rule was used to guide the admission decision rule, 57% of the low-risk patients were discharged, compared to only 42% in a preceding period when clinical judgment was used [43]. However, in the period when the prediction rule was used, 9% of the discharged patients failed outpatient therapy, whereas no patients fell into this category during the period when clinical judgment was used to make this decision. In another study, 70% of low-risk patients were sent home when the admission decision rule was applied, compared to approximately 50% when clinical judgment was used [44]. Thus, in both studies, clinical judgment (probably appropriately) led to many patients being admitted, in spite of the model suggesting that they be discharged. One problem with the PORT model is that points are assigned on the basis of dichotomous variables, and thus if vital sign abnormalities are present but below the threshold for assigning points, severity of illness can be underestimated. The cut-oﬀ points in this model are heart rate greater than 125/min, respiratory rate greater than 30/min, systolic blood pressure less than 90 mm Hg, fever under 35j or over 40jC, PaO2 less than 60 mm Hg, BUN greater than 30 mg/dL, and glucose greater than 250 mg/ dL [40]. Another limitation of the PORT model is that points are based on age and comorbid illness, and older patients will often have a high score, even if

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the illness is mild. Thus, in one recent study, when elderly individuals with CAP were admitted, most fell into risk classes III through V, and the risk of death increased along with the category [45]. However, it is uncertain how many older patients in higher risk classes can be safely managed out of the hospital. Recently, Lim et al. have shown that the BTS rule does not work as well in the elderly as in younger patients, reﬂecting the altered clinical presentations of pneumonia in this population. In one study, the rule had a 66% sensitivity and a 73% speciﬁcity for predicting mortality in a population that included 48% who were at least 75 years of age [46,47]. The BTS rule may be useful for avoiding the problem of overlooking a sick patient: in one study, the BTS critieria identiﬁed 19 of 20 patients, in a population of 255, who were destined to die, whereas clinical criteria identiﬁed only 12 of the 19 as being seriously ill [42]. However, the BTS rule may not be optimal in an elderly population, and in recent studies, it did not work as well as it did in other populations, although it had a higher sensitivity for predicting mortality than the Prognostic Scoring Index (PSI), derived from the PORT study [40,46]. It is clear that all rules can be problematic, and thus the admission decision remains a clinical judgment. Need for ICU Care There is no speciﬁc rule for who should be admitted to the ICU, but in general the ICU is used for approximately 10% of all admitted CAP patients, and this population has a mortality rate of at least 30%, compared to a mortality rate of 12% for all admitted patients [48]. There is some uncertainty about the beneﬁt of ICU care for patients with CAP, but mortality rates are lower if patients are admitted early in the course of severe illness than if they are admitted only after the onset of respiratory failure [49]. The 1993 ATS guidelines used data from the literature to deﬁne 10 criteria for severe CAP, saying that the ICU admission was needed for anyone having one of these features present [50]. However, subsequent studies demonstrated that this deﬁnition was too inclusive, and 65% of all admitted CAP patients (not needing ICU care) met one of these criteria [51]. To better deﬁne the need for ICU care in CAP, Ewig et al. applied these 10 criteria to 64 patients who were admitted to the ICU and compared the ﬁndings to those in 331 patients admitted to the hospital but not the ICU [51]. With this approach, a better deﬁnition of severe CAP was derived, with a sensitivity of 78%, a speciﬁcity of 94%, a positive predictive value of 75%, and a negative predictive value of 95%. This deﬁnition required the presence of either two of three ‘‘minor criteria’’ present on admission, or one of two ‘‘major criteria’’ present on admission or later in the hospital course. The minor criteria were systolic blood pressure lower than 90 mm Hg, PaO2/FiO2 ratio

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less than 250, or multilobar inﬁltrates. The major criteria were need for mechanical ventilation or septic shock. In a subsequent study of 1339 patients, 170 were admitted to the ICU and no prediction rule was completely accurate for deciding need for ICU admission [52]. Overall the presence of one of two major criteria or two of three minor criteria was the most accurate rule, with a sensitivity of 71% and a speciﬁcity of 72% and a negative predictive value of 94%. A high score using the PORT model had a speciﬁcity of only 50% for deﬁning need for ICU admission [52]. As discussed above, another way to identify patients with more severe illness is to apply the BTS rule in its original or modiﬁed version, but this approach had a sensitivity of 40% and a speciﬁcity of 78% when used to deﬁne need for ICU admission [52]. In the future, we will need to determine if there is a better way to prospectively deﬁne the need for ICU admission. DIAGNOSTIC TESTING (Table 4) Once the history and physical examination suggest the presence of pneumonia, the diagnosis should be conﬁrmed by chest radiograph. Although some patients may have clinical ﬁndings of pneumonia (focal crackles, bronchial breath sounds), and a negative chest radiograph, the need for antibiotic therapy of CAP has been established in patients with a radiographic inﬁltrate. In some patients, ﬁndings of pneumonia may be present, but the chest radiograph is negative, and the correct diagnosis is bronchitis, an illness that may not require antibiotic therapy, unless patients have chronic underlying lung disease. However, in other populations, such as the elderly and chronically ill, the clinical diagnosis is diﬃcult, and these patients can have pneumonia but present only with nonrespiratory ﬁndings; for these individuals, a chest radiograph is essential to deﬁne the presence of parenchymal lung infection. A chest radiograph not only conﬁrms the presence of pneumonia but can be used to identify complicated illness and to grade severity of disease, by noting such ﬁndings as pleural eﬀusion and multilobar illness [1]. Although deﬁning a speciﬁc etiologic diagnosis of CAP allows for focused antibiotic therapy, most patients do not have a speciﬁc pathogen identiﬁed, and many who do, have this diagnosis made days or weeks later, as the results of cultures or serologic testing become available. In addition, recent studies have emphasized the mortality beneﬁt of prompt administration of eﬀective antibiotic therapy, with a goal of administering intravenous antibiotics within 8 hours of admission to the hospital, for those with moderate to severe illness [53]. Thus, therapy should never be delayed for the purpose of diagnostic testing, and the diagnostic workup should be streamlined, with all patients receiving empiric therapy based on algorithms as soon as possible. With such empiric regimens, as many as 90% of admitted patients will have a prompt response to therapy [54].

Treatment of Hospitalized CAP Patients

TABLE 4

293

Diagnostic Testing for CAP

Test Chest radiograph CT scan

Blood cultures

Sputum Gram stain

Sputum culture

Oximetry or arterial blood gas Serologic testing for Legionella, C. pneumoniae, M. pneumoniae, viruses Legionella urinary antigen

Comment CT scan may show infiltrates that are absent on routine radiograph Not a routine test, but can be used in nonresponding patients to identify cavitation or loculated pleural fluid. Contrast study can demonstrate pulmonary embolus Pneumococcus is the usual organism (in 50–80% of positive samples). Can define antibiotic susceptibility pattern. Patients are rarely able to give an adequate specimen. Can correlate with sputum culture to define predominant organism and can use to identify unsuspected pathogens Use if suspect drug-resistant or unusual pathogen, but positive result cannot separate colonization from infection Both tests define severity of infection and the need for oxygen; a blood gas should be done if hypercarbia is suspected. Usually requires acute and convalescent titers collected 4–6 weeks apart, and is impractical for guiding management

Specific to serogroup 1, but the best diagnostic test for Legionella at the time of admission

Recommended testing for admitted patients includes a chest radiograph, assessment of oxygenation (pulse oximetry or blood gas, the latter if retention of carbon dioxide is suspected), routine admission blood work and two sets of blood cultures [1]. If the patient has a pleural eﬀusion, this should be tapped and the ﬂuid sent for culture and biochemical analysis. Although blood cultures are positive in only 10–20% of CAP patients, they can be used to deﬁne a speciﬁc diagnosis and to deﬁne the presence of drug- resistant pneumococci [21]. Sputum culture should be limited to patients suspected of having an infection with a drug-resistant or unusual pathogen. The role of gram stain of sputum to guide initial antibiotic therapy is controversial, but this test can guide the interpretation of sputum culture results by deﬁning the predominant organism present in the sample. The role of gram stain in focusing initial antibiotic therapy is uncertain because the accuracy of the test to predict the culture recovery of an organism such as

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pneumococcus depends on the criteria used. If the ﬁnding of any grampositive diplococcus is used to deﬁne a positive test, then the test will be sensitive but not very speciﬁc. On the other hand, the ﬁnding of a predominance of gram-positive diplococci will be speciﬁc, but not sensitive, for predicting the culture recovery of pneumococcus [1,55]. In a recent study, the practical limitations of the test were demonstrated: out of 116 patients with CAP, only 42 could produce a sputum sample of which 23 were valid, and only 10 samples were diagnostic, with antibiotics directed to the diagnostic result in only one patient [56]. Even if gram stain ﬁndings were used to focus antibiotic therapy, this would not allow for empiric coverage of mixed infection with both bacteria and atypical pathogens. In the ATS guidelines, the recommendation is to use the gram stain to broaden initial empiric therapy, if the ﬁndings suggest an organism that is not covered in routine empiric therapy (such as S. aureus being suggested by the presence of clusters of gram-positive cocci, during a time of epidemic inﬂuenza) [1]. Routine serologic testing is not recommended. However, in patients with severe illness, the diagnosis of Legionella infection can be made by urinary antigen testing, which is the test that is most likely to be positive at the time of admission, but it is a test that is speciﬁc only for serogroup I infection [57]. Commercially available tests for pneumococcal urinary antigen have been developed, but their role in the clinical management of CAP has not been deﬁned. Bronchoscopy is not indicated as a routine diagnostic test and should be restricted to immune-compromised patients, and to selected individuals with severe forms of CAP.

THERAPY OF CAP General Principles The goal of empiric therapy of patients with CAP is to target the likely etiologic pathogens by categorizing patients on the basis of place of therapy (inpatient, ICU), severity of illness, and the presence or absence of cardiopulmonary disease or speciﬁc ‘‘modifying’’ factors. By using these factors, a set of likely pathogens can be predicted for each patient (Table 2), and this information can be used to guide initial empiric therapy. If a speciﬁc pathogen is subsequently identiﬁed by diagnostic testing, then therapy can be focused. In choosing empiric therapy of CAP, certain principles should be followed, as outlined in Table 5 [1,58]. For the non-ICU inpatient therapy can be an intravenous macrolide (azithromycin) alone, provided that the patient has no underlying cardiopulmonary disease and no risk factors for infection with DRSP, enteric gram-negatives, or anaerobes. Although very

Treatment of Hospitalized CAP Patients

TABLE 5

295

Principles in Antibiotic Therapy of CAP

Principle Administer first dose of antibiotics within 8 hr of arrival in hospital Treat all patients for the possibility of infection with ‘‘atypical pathogens’’ and pneumococcus Monotherapy with a macolide can be given to inpatients with no risk factors for DRSP, gram-negatives or aspiration For inpatients with risk factors for DRSP and/or gram-negatives, use either a h-lactam/macrolide combination or monotherapy with an anti-pneumococcal quinolone. Quinolone therapy should be used in penicillin-allergic patients. For inpatients with clinical risks for DRSP intravenous h-lactam therapy should be with either cefotaxime, cefriaxone, ampicillin/sulbactam, or high-dose ampicillin Limit anti-pseudomonal antibiotics to patients with pseudomonal risk factors For severe CAP, use a h-lactam with either a macrolide or a quinolone, but no patient should get quinolone monotherapy Limit the use of vancomycin to empiric therapy of patients with severe illness, especially with suspected meningitis

few patients of this type are admitted to the hospital, macrolide monotherapy has been documented to be eﬀective in this population and may be more costeﬀective than combination therapy [59,60]. The majority of admitted patients will have cardiopulmonary disease and/or modifying factors, and they can be treated with either a selected (see Table 5) intravenous h-lactam combined with a macrolide, or they can receive an intravenous antipneumococcal quinolone (gatiﬂoxacin, levoﬂoxacin, moxiﬂoxacin) alone. From the available data, it appears that either regimen is therapeutically equivalent; and although not proven, it may be useful to use these two types of regimens interchangeably, striving for ‘‘antibiotic heterogeneity’’ in the hospital, so that one regimen is not used exclusively in all patients [1]. This type of approach has the theoretic advantage of minimizing selection pressure for antibiotic resistance. Although oral quinolones may be as eﬀective as intravenous quinolones for admitted patients with moderately severe illness, all admitted patients should receive initial therapy intravenously to be sure that the medication has been absorbed [1]. Once the patient shows a good clinical response (deﬁned below), oral therapy can be started. Selected inpatients with mild to moderate disease can initially be treated with the combination of an intravenous hlactam and an oral macrolide, switching to exclusively oral therapy once the patient shows a good clinical response.

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In the ICU population, all individuals should be treated for DRSP and atypical pathogens, but only those with appropriate risk factors (above) should have coverage for P. aeruginosa [1]. The eﬃcacy, dosing, and safety of quinolone monotherapy has not been established for ICU-admitted CAP patients, so the therapy for such patients, in the absence of pseudomonal risk factors, should be a selected intravenous h-lactam, combined with either an intravenous macrolide or an intravenous quinolone. For patients with pseudomonal risk factors, therapy can be with a two-drug regimen, using an anti-pseudomonal h-lactam (cefepime, imipenem, meropenem, piperacillin/ tazobactam) plus ciproﬂoxacin (the only anti-pseudomonal quinolone); or alternatively with a three-drug regimen, using an anti-pseudomonal h-lactam plus an aminoglycoside plus either an intravenous non-pseudomonal quinolone or macrolide. In a study of patients admitted to the ICU with severe CAP, mortality was reduced whenever a macrolide was included, which was usually in combination with a h-lactam (either a cephalosporin or h-lactam/ h-lactamase inhibitor) [61]. Similar outcome was seen with quinolone monotherapy, although few patients received this regimen, and thus it should not be used until more patients have been studied using this regimen [61]. The existing guideline recommendations for the therapy of CAP in inpatients on the medical ward, or in the ICU, are summarized in Table 6 [58]. The anti-pneumococcal quinolones have assumed great importance in the therapy of CAP because it is possible to cover pneumococcus (including DRSP), gram-negatives, and atypical pathogens with a single drug, given once daily. Quinolones penetrate well into respiratory secretions and are highly bioavailable, achieving the same serum levels with oral or intravenous therapy, thereby allowing a rapid switch from intravenous to oral antibiotic therapy. The possibility of quinolones promoting an early switch from intravenous to oral therapy was demonstrated in a study comparing moxiﬂoxacin to a h-lactam/h-lactamase inhibitor, with or without a macrolide. In that study, therapy with the quinolone was associated with signiﬁcantly more patients being afebrile at day 2 and switching to oral therapy by day 3 than those receiving the comparator regimen (50% vs. 18%) [62]. Although all of the anti-pneumococcal quinolones are available orally and intravenously, and all have been eﬀective for the therapy of CAP, there are diﬀerences among the available agents in their intrinsic activity against pneumococcus [1,63,64]. Based on the minimum inhibitory concentration (MIC) against S. pneumoniae, these agents can be ranked, from most to least active, as moxiﬂoxacin, gatiﬂoxacin, and levoﬂoxacin. Some data suggest a lower likelihood of both clinical failures and the induction of pneumoccal resistance to quinolones, if the more active agents are used in place of the less active agents [64,65]. In addition, there are now reports of failures in pneumococcal pneumonia with levoﬂoxacin, and these have occurred in

Treatment of Hospitalized CAP Patients

TABLE 6

297

In-patient Therapy of CAP in Existing Guidelines

Non-ICU IDSA 2000a: Selected h-lactam plus a macrolide or monotherapy with a respiratory fluoroquinolone No preference for either regimen Canadian Consensus 2000b: Respiratory fluroquinolone or Second-, third-, or fourth-generation cephalosporin plus a macrolide Quinolone as first choice CDC 2000c: Selected h-lactam plus a macrolide or Monotherapy with a respiratory fluoroquinolone Quinolone to be used only if h-lactam allergic, h-lactam failure, or documented high-level penicillin resistance. ATS 2001d: No cardiopulmonary disease or modifying factors: IV azithromycin Cardiopulmonary disease or modifying factors: Selected h-lactam plus a macrolide or tetracycline or monotherapy with a fluoroquinolone No preference for either regimen ICU IDSA 2000a No structural lung disease: h-Lactam plus either a respiratory fluoroquinolone or a macrolide Structural lung disease: Anti-pseudomonal h-lactam plus a fluoroquinolone Canadian Consensus 2000b: No pseudomonal risks: Cefotaxime, ceftriaxone, h-lactam/h-lactamase inhibitor plus either a respiratory fluoroquinolone or a macrolide Pseudomonal risks: 1. Ciprofloxacin plus either an anti-pseudomonal h-lactam or aminoglycoside 2. Anti-pseudomonal h-lactam plus aminoglycoside plus macrolide CDC 2000c: h-Lactam plus either a macrolide or fluoroquinolone ATS 2001d: No pseudomonal risks: h-Lactam plus either a macrolide or respiratory fluoroquinolone Pseudomonal risks: 1. Anti-pseudomonal h-lactam plus ciprofloxacin 2. Anti-pseudomonal h-lactam plus aminoglycoside plus either respiratory fluroquinolone or a macrolide Note: Selected h-lactams are listed in Table 5. In the ATS guidelines, anti-pseudomonal agents (cefepime, piperacillin-tazobactam, imipenem, meropenem) are only to be used if pseudomonal risk factors are present (generally ICU patients), but the IDSA and Canadian guidelines permit some of these agents in non-ICU patients. a Ref. 14. b Ref. 21. c Ref. 76. d Ref 1.

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patients who were infected with levoﬂoxacin-resistant organisms, after a recent course of quionolone therapy or who acquired this resistance during therapy (after having an initially sensitive organism) [65,66]. Based on these data, and on the ﬁnding that recent therapy with a macrolide, h-lactam, or quinolone can predispose to resistance to other agents in the same class, a recent history of antibiotic therapy should guide initial therapy selection. If the patient has been on any antibiotic in the past 3 months, it may be preferable to choose an agent in a totally diﬀerent therapeutic class for CAP therapy. In addition to the general approach to therapy outlined above, there are several other therapeutic issues to consider in the management of CAP. Timing of Initial Antibiotic Therapy For inpatients with CAP, the use of timely and accurate therapy is essential to reduce mortality. In patients with severe CAP, improved survival has occurred if initial empiric therapy is accurate and if it leads to a rapid clinical response [67]. In one study, if initial therapy led to a clinical response within 72 hr, mortality of severe CAP was approximately 10%, compared to a mortality rate of 60% in patients who had initially ineﬀective therapy [67]. Another recent ﬁnding is the need to provide initial intravenous antibiotic therapy within 8 hr of the patient’s arrival at the hospital [53]. In a large Medicare study of 14,069 patients, mortality at 30 days was signiﬁcantly reduced for the 75% of patients who received their ﬁrst dose of therapy within 8 hr of coming to the hospital [53]. Although this has become the target time frame for initial therapy, there was additional beneﬁt for therapy given even sooner. To achieve the goal of early therapy, it may be necessary to assure that the ﬁrst dose of antibiotics is administered in the emergency department. In one study of 700 patients with CAP, length of stay was signiﬁcantly reduced in patients who received the ﬁrst dose of antibiotic therapy in the emergency department rather than the medical ﬂoor. Patients treated in the emergency department received therapy at a mean of 3.5 hr, compared to a mean of 9.5 hr for those ﬁrst treated on the medical ﬂoor [68]. The Role of Routine Therapy for Atypical Pathogens in All Hospitalized Patients In most available North American guidelines, initial empiric therapy of CAP provides for all inpatients to be treated for the possibility of atypical pathogen infection, either as primary infection, or as part of a mixed infection [1,14,21]. A number of outcome studies of large populations, of primarily inpatients, have shown that when therapy includes a macrolide or a quinolone, outcomes

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299

(including mortality) are improved, compared to when a h-lactam is used by itself [34,35]. In one study of 13,000 Medicare patients, mortality at 30 days was reduced if a macrolide was added to a second- or third-generation cephalosporin, or a quinolone was used alone, compared to therapy with a third-generation cephalosporin by itself [34]. These ﬁndings support a potentially important role for atypical pathogens and may explain the ﬁndings of one recent study that mortality is increased for patients with bacteremic pneumococcal pneumonia when a single eﬀective agent was used, compared to dual eﬀective therapy [69]. In that study, it is of interest that monotherapy with a third-generation cephalosporin was associated with a higher mortality than if the same agent was used along with an agent that provided atypical pathogen coverage (i.e., a macrolide or quinolone), implying that coinfection with atypical pathogens may even be important in patients with bacteremic pneumococcal pneumonia. The Role of DRSP in the Empiric Therapy of CAP As discussed above, both the ATS and IDSA guidelines have identiﬁed risk factors for infection with DRSP, but the IDSA approach is to treat all inpatients for the possibility of DRSP, whereas the ATS approach is to use these risk factors to decide which inpatients should be targeted for DRSP and which do not need this therapy [1,14]. If an inpatient is at risk for infection with DRSP, therapy should be with any of the following intravenous agents: cefotaxime, ceftriaxone, ampicillin/sulbactam, high-dose ampicillin, or an anti-pneumococcal quinolone (considering the issues mentioned above). When a h-lactam is used, a macrolide should be added for the reasons previously discussed. The rationale for using speciﬁc agents in patients with risk factors for DRSP is not only to minimize the risk of treatment failure, but also to rapidly and reliably eradicate pneumococcal organisms that have low levels of resistance, so that there is less selection pressure for emergence of organisms with high-level resistance. It is unlikely that targeting at-risk patients with highly active regimens will improve outcomes, because the clinically relevant level of pneumococcal resistance is a penicillin MIC value of at least 4 mg/L, a level of resistance that is relatively uncommon today [22,23]. The clinical relevance of cephalosporin resistance is also being studied. Recently, the breakpoints for deﬁning cephalosporin-resistant pneumococci have been changed to an MIC of at least 4 mg/L for nonmeningeal infection. Pallares et al. found that when ceftriaxone or cefotaxime were used to treat organisms having MIC values up to 2 mg/L, the outcome was the same as if the organisms were not resistant. If penicillins were used for DRSP organisms, the mortality was higher than if the same therapy was used for sensitive

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organisms. However, cefotaxime and ceftriaxone were eﬀective for penicillinresistant organisms [70]. EVALUATION OF RESPONSE TO THERAPY The majority of outpatients and inpatients will respond rapidly to the empiric therapy regimens suggested above, with clinical response usually occurring within 24 to 72 hours [1,71]. Clinical response for inpatients is deﬁned as improvement in symptoms of cough, sputum production, and dyspnea, along with ability to take medications by mouth, declining white blood cell count, and an afebrile status for at least two occasions 8 hr apart. When a patient has met these criteria for clinical response, it is appropriate to switch to an oral therapy regimen and to discharge the patient, if he or she is otherwise medically and socially stable [1,71,72]. Observation in the hospital during oral therapy is generally not necessary, since patients usually do not have clinical deterioration after reaching signs of stability and after being able to switch to oral therapy [72]. If patients are discharged when not clinically stable, there is an increased risk of mortality and readmission [73]. In one study, instability was deﬁned as any of the following within 24 hours of discharge: fever higher than 37.8jC, HR greater than 100/min, respiratory rate greater than 24/min, systolic BP less than 90 mm Hg, oxygen saturation less than 90%, inability to maintain oral intake, and abnormal mental status. Readmission or death was at least 3 times more likely for patients with at least two of these factors present, compared to none or one factor present, but only 2% of patients fell into this category [73]. Radiographic improvement lags behind clinical improvement, and in a responding patient, a repeat chest radiograph is not necessary until 2 to 4 weeks after starting therapy. In general, 50% of patients with pneumococcal pneumonia have radiographic clearing at 5 weeks, with the majority clear in 2 to 3 months. With bacteremic disease, 50% have clear chest radiographs at 9 weeks, and most are clear by 18 weeks [74,75]. Radiographic resolution in community-acquired pneumonia is most inﬂuenced by the number of lobes involved and the age of the patient. Radiographic clearance of communityacquired pneumonia decreases by 20% per decade, after age 20, and patients with multilobar inﬁltrates take longer to clear than those with unilobar disease [74]. If the patient fails to respond to therapy in the expected time interval, then it is necessary to consider infection with a drug-resistant or unusual pathogen (tuberculosis, anthrax, C. burnetii, Burkholderia pseudomallei, C. psittaci, Pasteurella multocida, endemic fungi, or viruses); a pneumonic complication (lung abscess, endocarditis, empyema); or a noninfectious process that mimics pneumonia (bronchiolitis obliterans with organizing pneumonia, hypersensitivity pneumonitis, pulmonary vasculitis, bronchoalveolar cell

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70. Pallares R, Capdevila O, Linares J, Grau I, Onaga H, Tubau F, Schulze MH, Hohl P, Gudiol F. The eﬀect of cephalosporin resistance on mortality in adult patients with nonmeningeal systemic pneumococcal infections. Am J Med 2002; 113:120–126. 71. Ramirez JA, Vargas S, Ritter GW, Brier ME, Wright A, Smith S, et al. Early switch from intravenous to oral antibiotics and early hospital discharge: a prospective observational study of 200 consecutive patients with communityacquired pneumonia. Arch Intern Med 1999; 159:2449–2454. 72. Rhew DC, Hackner D, Henderson L, Ellrodt AG, Weingarten SR. The clinical beneﬁt of in-hospital observation in ‘‘low risk’’ pneumonia patients after conversion from parenteral to oral antimicrobial therapy. Chest 1998; 113:142–146. 73. Halm EA, Fine MJ, Kapoor WN, Singer DE, Marrie TJ, Siu AL. Instability on hospital discharge and the risk of adverse outcomes in patients with pneumonia. Arch Intern Med 2002; 162:1278–1284. 74. Mittl RL, Schwab RJ, Duchin JS, et al. Radiographic resolution of communityacquired pneumonia. Am J Respir Crit Care Med 1994; 149:630–635. 75. Jay S, Johanson W, Pierce A. The radiologic resolution of streptococcal pneumoniae pneumonia. N Engl J Med 1975; 293:798–801. 76. Heﬄeﬁnger JD, Dowell SF, Jorgensen JH, et al. Management of communityacquired pneumonia in the era of pneumococcal resistance: a report from the drug-resistant Streptococcus pneumoniae Therapeutic Working Group. Arch Intern Med 2000; 160:1399–1408.

15 Anaerobic Pleuropulmonary Infection Matthew E. Levison Drexel University College of Medicine Medical College of Pennsylvania Hospital Philadelphia, Pennsylvania, U.S.A.

INTRODUCTION Bacteria can be classiﬁed by the type of oxidation-reduction reactions used to generate energy needed for growth and multiplication. Anaerobic bacteria are grouped as facultative, microaerophilic, or obligate anaerobes, depending on their degree of oxygen tolerance. Facultative anaerobes tolerate the presence or absence of oxygen, and microaerophils tolerate only no or low concentrations of oxygen. Obligate anaerobes, however, cannot survive long even when exposed to very low concentrations of oxygen. Indeed, obligate anaerobes tolerate only an environment with an oxidizing capacity (as measured by the redox potential) lower than would occur following total removal of oxygen; these very low redox potentials result from the additional presence of reducing agents, such as devitalized tissue in vivo. Similarly, devitalized tissue (e.g., chopped meat or liver) or reducing agents (cysteine or thioglycollate) are used in culture systems to lower the redox potential suﬃciently to permit growth of obligate anaerobes in vitro. Obligate anaerobes are the predominant constituents of the normal microﬂora of the gingival crevice. The crevicular microﬂora is a complex ecosystem composed 307

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of several hundred diﬀerent bacterial species. Its bacterial density approximates that of solid packed bacteria, as are found in colonies growing on an agar plate (i.e., 1012 colony-forming units [CFU]/gram). The crevicular microﬂora is normally predominantly gram-positive and the predominant anaerobic bacterial species is Actinomyces; but in the presence of periodontitis, the gingival crevice deepens as the epidermal dentine junction recedes toward the tooth apex. The bacterial microﬂora in the abnormal periodontal pocket becomes predominantly gram-negative, and the predominant anaerobic bacterial species are Porphyromonas, Prevotella, Bacteroides, and Fusobacterium species [1]. Saliva that bathes these surfaces contains gingival crevice microorganisms in addition to organisms that colonize the nasopharynx, tongue, and buccal mucosa, such as viridans streptococci and known aerobic pulmonary pathogens, such as Streptococcus pneumoniae and Hemophilus inﬂuenzae. PATHOGENESIS Anaerobic pulmonary infection usually is acquired by aspiration of oropharyngeal contents that includes these salivary microorganisms. Aspiration occurs among normal people, especially during deep sleep, but in certain patients aspiration is thought to be of suﬃcient magnitude or the aspirated material may contain adjuvants, such as necrotic tissue, food or foreign bodies, or particularly virulent pathogens or synergistic combinations of microorganisms to overcome lung defenses. However, the virulence of the organism is usually less important in the pathogenesis of anaerobic infection than defects in host defenses—for example, a predisposition to aspirate (such as occurs after a loss of consciousness from epilepsy, diabetic coma, general anesthesia, head trauma, or intoxication because of alcoholism or other drug abuse or overdose, or with a neurologic disorder of swallowing or with esophageal diseases) and periodontal disease that would favor the presence of large numbers of potential anaerobic pathogens and possibly necrotic periodontal debris in aspirated oropharyngeal secretions. Anaerobic pulmonary infection is less common among edentulous individuals. Indeed, the development of primary anaerobic pulmonary infection in edentulous patients should prompt a search for a neoplastic process in the nasopharynx or lower respiratory tract that would result in endobronchial obstruction and provide a focus of anaerobic microbial proliferation in necrotic neoplastic tissue. Anaerobic pulmonary infection developing as a consequence of bronchogenic spread to the lung of endogenous microorganisms in the oropharyngeal microﬂora is usually referred to as primary. Hematogenous anaerobic pulmonary infection is referred to as secondary, because in this instance the primary infection (bacteremia, endocarditis, or suppurative thrombophlebi-

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tis, be it jugular or pelvic) will usually be clinically evident. Unresolved anaerobic bacterial pneumonitis will undergo necrosis in 1 to 2 weeks and result in one or more discrete cavities. The necrotizing infection is referred to as a lung abscess if each cavity is 2 cm or more in diameter. If there are multiple, small cavities, each less than 2 cm in diameter, the process is usually referred to as necrotizing pneumonia. Both lung abscess and necrotizing pneumonia are thought to be diﬀerent manifestations of the same pathogenetic processes. Extension of the anaerobic pulmonary infection to the pleural space may result in anaerobic empyema. MICROBIOLOGY When microorganisms are aspirated into the lower respiratory tract, there is a marked simpliﬁcation of the ﬂora, so that only about four or ﬁve microbial species are isolated from minimally contaminated lower respiratory secretions in these patients. The pathogenic obligate anaerobes are usually more oxygentolerant than most obligate anaerobic members of the microﬂora. Anaerobic species, such as Prevotella melaninogenica, Fusobacterium nucleatum, and Peptostreptococcus species, usually predominate [2]. Microaerophilic and facultative streptococci are also frequently present. In some patients, the obligate anaerobes may be mixed with facultative respiratory pathogens, such as S. pneumoniae, Staphylococcus aureus, H. inﬂuenzae, or Klebsiella pneumoniae. The obligate anaerobic species, unlike facultative microorganisms, typically produce a foul odor in clinical specimens, in part due to various volatile short chain fatty acids. Bacteriologic studies in the early 1970s of lower respiratory tract secretions obtained by methods (such as transtracheal aspiration that minimize contamination with oropharyngeal microbial ﬂora), established that polymicrobial anaerobic bacterial ﬂora are the cause of the infection in about one-third of patients with community-acquired pneumonia, one-third of non-intubated patients with nosocomial pneumonia, and in most patients with putrid lung abscess [3–8]. In a more recent study that used ﬁberoptic bronchoscopy and protected specimen brush to obtain samples from the involved area of lung prior to antimicrobial therapy [9], pathogens were recovered in 96% of patients with pneumonia and obligate anaerobes in 46% of these patients. Ventilator-associated pneumonia (VAP) is also thought to result from aspiration of oropharyngeal material. Indeed, using rigorous anaerobic methods and protected specimen brush sampling within 24 hr after development of pneumonia, anaerobes have been found in 23% of patients with VAP [10]. However, other studies using ﬁberoptic bronchoscopy and protected specimen brush to obtain cultures have failed to recover anaerobes in aspiration pneumonia and VAP [11,12], perhaps because the

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patients in these studies received antibiotic therapy prior to bacteriologic sampling [12]. ACTINOMYCOSIS Actinomyces species, which are part of the normal gingival, intestinal, and vaginal ﬂora, can produce a clinically distinct endogenous craniofacial, thoracic, abdominal, or pelvic infection. Actinomycosis is often polymicrobial, and the copathogens include anaerobic cocci, Prevotella, and Actinobacillus actinomycetemcomitans (microaerophilic gram-negative bacillus), and Hemophilus species. Actinomyces is an obligate anaerobic, delicate, ﬁlamentous gram-positive bacillus that branches to form Y, V, or T conﬁgurations and is often beaded. The bacilli are non–acid-fast, unlike the obligate aerobe, Nocardia, which they otherwise resemble morphologically. Colonies may appear in cultures, pus, and tissue as hard white-yellow granules, the socalled sulfur granule, which is 1–2 mm in diameter and composed of a mass of tangled ﬁlaments cemented together by a matrix secreted by the organism. Routes of infection for thoracic actinomycosis include aspiration of oral contents or contiguous spread from craniofacial or abdominal-pelvic foci. Thoracic actinomycosis is characterized pathologically by the presence of sulfur granules and chronic inﬂammation, necrosis, and ﬁbrosis, which crosses adjacent tissue plains and may involve contiguous regions of lung, pleura, ribs, vertebrae, mediastinum, esophagus, pericardium, and subcutaneous tissue, eventually to drain via multiple cutaneous sinuses on the chest wall. Hematogenous dissemination from the primary location can also occur. EMPYEMA Empyema can occur by contiguous spread from the infected lung or by hematogenous dissemination. Obligate anaerobes account for 25–40% of cases in most studies of empyema; the highest reported frequency of 76% was from a series of patients with empyema from a large city hospital and two Veterans Aﬀairs hospitals [13]. CLINICAL PRESENTATION The clinical presentation of aspiration pneumonia is usually acute and similar to that of pneumococcal pneumonia. However, about three-quarters of patients with primary lung abscess have an indolent febrile, wasting illness with respiratory symptoms (cough, sputum production, pleuritic chest pain, blood-streaked sputum) of several weeks duration, similar to that of tuber-

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culosis or lung cancer, except over 50% of patients with lung abscess will produce sputum that has a foul odor or complain of a foul odor to their breath (although in early infection the putrid odor is often absent). One-quarter of patients with lung abscess will present with a more acute illness similar to that of pneumococcal pneumonia. Actinomycosis presents clinically as a chronic wasting febrile illness with pleuritic chest pain and cough productive of purulent, and, at times, blood-tinged sputum. DIAGNOSIS The anaerobic etiology of aspiration pulmonary infection is frequently presumptive and its therapy is consequently empirical because of the diﬃculties in obtaining uncontaminated respiratory secretions from the lung, in recovering of obligate anaerobes from clinical specimens, and in determining of antimicrobial susceptibility of the anaerobic isolates [14]. Patients who present with typical features of lung abscess that include a predisposition for aspiration, periodontal disease, a sputum with foul odor, one or more thickwalled cavities in dependent bronchopulmonary segments (e.g., superior segment of the lower lobe or posterior segment of the upper lobe when aspirating in the supine position), with air-ﬂuid levels, should need little further initial diagnostic work-up and be treated presumptively for a polymicobial anaerobic infection. Although of no value for detecting anaerobes, culture of expectorated sputum is useful for excluding the presence of other pulmonary pathogens. Febrile patients should also have blood cultures to identify possible hematogenous anaerobic pneumonia (e.g. Lemierre’s syndrome; i.e., Fusobacterium bacteremia, septic pulmonary emboli, and suppurative jugular thrombophlebitis) or exclude aerobic or facultative organisms capable of causing lung abscess (e.g., S. aureus). Pleural ﬂuid, if present, should also be obtained for stains and cultures. Upper lobe cavities without air-ﬂuid levels suggest tuberculosis and require exclusion of M. tuberculosis with three morning sputum collections for mycobacterial stains and cultures. Also, in patients who fail to respond to empirical therapy for putative anaerobic pneumonia, in patients suspected of pulmonary neoplasm, and in immunocompromised patients, more rigorous diagnostic testing is usually indicated; such testing includes bronchoscopy, protected brushing, and collection of bronchoalveolar lavage ﬂuid for stains and cultures for routine bacteria, Rhodococcus equi (in patients with AIDS), legionella, nocardia and fungi, if expectorated sputum studies fail to disclose the presence of these organisms. Computed tomography (CT) of the chest may be important to deﬁne pathologic anatomy in patients with a pyopneumothorax. CT, bronchoscopy, and biopsy may also be necessary in some patients, especially those who do not respond to empirical therapy for lung

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abscess to exclude conditions such as cystic bronchiectasis, cavitating neoplasms, and Wegener’s granulomatosis, which may also produce cavitation and be confused with lung abscess.

ANTIMICROBIAL TREATMENT Older Antimicrobial Agents Penicillin, either 500–750 mg every 6 hours orally or 10–20 million unit intravenously per day, or tetracycline had been the standard antimicrobial agents used in empirical regimens to treat putative anaerobic lung abscess [13]. However, many obligate anaerobic gram-negative respiratory pathogens are now found to be penicillin-resistant as a consequence of h-lactamase production [9] and are also tetracycline-resistant. Indeed, two studies comparing penicillin to clindamycin in the treatment of putrid lung abscess found shorter time to defervescence and time to loss of the putrid odor to the sputum and less frequent relapse with clindamycin [15,16]. Clindamycin can be used intravenously in doses of 600 mg every 8 hr initially in hospitalized patients unable to tolerate oral therapy, or orally in doses of 300 mg every 6 hr. Other older agents that are active against both the oral anaerobes and microaerophilic streptococci include the carbapenems, (e.g., imipenem and meropenem), cefoxitin, and h-lactamase/h-lactam antibiotic combinations (e.g., amoxicillin/clavulanate, ampicillin/sulbactam, ticarcillin/clavulanate or piperacillin/tazobactam) [14,17,18]. These drugs, however, do not have the proven eﬃcacy of clindamycin, although susceptibility of anaerobes to clindamycin is no longer as predictable as when this drug was ﬁrst used [17]. Metronidazole, although it is reliably active against gram-negative anaerobes [17], has been found to be inadequate therapy for anaerobic pleuropulmonary infections when used alone [19], apparently because it is inactive against microaerophilic streptococci. Chloramphenicol is reliably active in vitro against anaerobes [14,17], and is eﬀective in treatment of anaerobic infections, but this drug is rarely used any longer because it can cause fatal aplastic anemia and alternative drugs are available. Actinomyces is susceptible to penicillin, ampicillin, cephalosporins, carbapenems, macrolides, tetracycline, and clindamycin. However, intravenous administration of high-dose penicillin G remains the treatment of choice (10–20 million units daily) for actinomycosis. The duration of intravenous therapy for actinomycosis is 4–6 weeks, especially when there is extensive tissue destruction, followed by oral administration of penicillin 2– 4 g daily or amoxicillin for up to one year to prevent relapse [20]. Tetracycline is an alternate option in patients allergic to penicillin. Antibiotic coverage of all the isolated pathogens involved in actinomycosis is often not necessary;

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however, if clindamycin is used alone and Actinobacillus is a copathogen, persistent infection can occur with this clindamycin–resistant organism. New Antimicrobial Agents: the Newer Fluoroquinolones, Ketolides, Oxazolidinones, and Carbapenems In addition to these older drugs, several new antimicrobial agents with in vitro activity against obligate anaerobes have been approved for treatment of respiratory tract infections because of demonstrated eﬃcacy in clinical trials of community-acquired pneumonia. However, none of these drugs have been studied in series of patients with bacteriologically conﬁrmed anaerobic pleuropulmonary infections, or with putative anaerobic infections, such as putrid lung abscess. These drugs have reliable activity against aerobic respiratory

TABLE 1

Antimicrobial Regimens to Treat Anaerobic Pleuropulmonary

Infectionsa Intravenous

Oral

Clindamycin Cefoxitin Amoxicillin plus metronidazole

600–900 mg q8h 2 g q8h

300 mg q6h

Ampicillin/sulbactamb

2 g ampicillin/1g sulbactam q6h

500 mg q8h or 875 mg q12h 500 mg q6h

Amoxicillin/clavulanateb

Piperacillin/tazobactamb Ticarcillin/clavulanateb Imipenemb Meropenemb Gatifloxacinb Moxifloxacinb Linezolidb a

875 mg amoxicillin/125 mg clavulanate q12h or 500 mg amoxicillin/125 mg clavulanate q8h 3 g piperacillin/0.375 g tazobactam q6h 3 g ticarcillin/1g clavulanate q6h 500 mg q6h 1 g q8h 400 mg q24h 400 mg q24h 600 mg q12h

400 mg q24h 400 mg q24h 600 mg q12h

Duration of therapy is at least 4–6 weeks. Intravenous can be switched to oral therapy when the patient has been afebrile for 4–5 days. b This antibiotic has not been approved by the FDA for treatment of pleuropulmonary infection caused by anaerobic bacteria.

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pathogens, such as S. pneumoniae, H. inﬂuenzae, and Moraxella catarrhalis, which have emerged resistant to the older agents. Except for ertapenem, they are also active against pathogens that cause the so-called atypical pneumonia syndrome (Chlamydia pneumoniae, Mycoplasma pneumoniae, and Legionella pneumophila). The in vitro activity demonstrated against a variety of anaerobic bacteria suggests that these drugs may have clinical eﬃcacy in anaerobic pleuropulmonary infections. However, the sources for isolates in these studies have not necessarily been lower respiratory tract secretions or pleural ﬂuid; when the source is other than pleuropulmonary, the published data may not be predictive of eﬃcacy for infection caused by anaerobic pleuropulmonary pathogens. New Fluoroquinolones The older ﬂuoroquinolones, such as ciproﬂoxacin, oﬂoxacin, and norﬂoxacin, are inactive against anaerobes. Trovaﬂoxacin, gatiﬂoxacin, moxiﬂoxacin, and gemiﬂoxacin, and to a limited extent levoﬂoxacin, are active against anaerobes [21–26]. Use of trovaﬂoxacin is now limited by the rare occurrence of hepatotoxicity that has been fatal in some cases. Side eﬀects with levoﬂoxacin, gatiﬂoxacin, and moxiﬂoxacin have been minimal, although prolongation of the QTc interval in some patients with sparﬂoxacin, gatiﬂoxacin, and moxiﬂoxacin has resulted in the recommendation that their use be avoided in patients with known prolongation of the QTc interval, in patients with uncorrected hypokalemia, and in patients receiving class 1A or class III antiarrhythmic agents. FDA approval of gemiﬂoxacin is still pending. Because of their broad spectrum of activity for respiratory pathogens and infrequency of signiﬁcant side eﬀects, these newer ﬂuoroquinolones have been used commonly for empirical therapy of community-acquired pneumonia. Indeed, the latest Infectious Disease Society of America (IDSA) guidelines for the treatment of community-acquired pneumonia [27] recommended their use, either (1) alone for treatment of outpatients or (2) combined with a h-lactam, such as ceftriaxone, for the treatment of patients requiring ICU admission. Combination therapy was recommended because eﬃcacy of the newer ﬂuoroquinolones when used alone in severe pneumonia has not been documented. For suspected aspiration, the IDSA recommended a newer ﬂuoroquinolone, with or without a h-lactam/h-lactamase inhibitor combination (such as ampicillin/sulbactam or piperacillin/tazobactam), metronidazole, or clindamycin. They speciﬁcally commented, though, that the newer ﬂuoroquinolones might not require additional anaerobic coverage, because of their in vitro activity against anaerobes. A CDC panel that was convened to consider treatment of communityacquired pneumonia in the face of emerging antimicrobial resistance was hesitant to recommend the newer ﬂuoroquinolones for fear that their wide-

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spread use may lead to development of ﬂuoroquinolone resistance among the respiratory pathogens (as well as other microorganisms that colonize the treated patients) [28]. The CDC panel did not speciﬁcally comment on treatment of anaerobic pulmonary infection. Ketolides The ketolides are a new family of antimicrobial agents that are structurally related to the macrolides. Their mechanism of action, similar to that of the macrolides, involves blocking protein synthesis by binding to the ribosomal RNA complex; but bacteria that either display MLSb type of resistance (i.e., cross-resistance to macrolides, clindamycin, and streptogramin B) as a result of decreased aﬃnity to an altered ribosomal target or display eﬄux type of resistance (i.e., resistance to macrolides, but susceptibility to clindamycin) are still susceptible to the ketolides. Telithromycin, a ketolide whose approval by the FDA for therapy of respiratory tract infection is pending, has been shown to be active against streptococci and staphylococci resistant to the macrolides. This ketolide is also active against many anaerobes, with minimal inhibitory concentrations (MIC) of V 0.5 Ag/mL [29]. Telithromycin is well absorbed and, when given in doses of 800 mg every 24 hr orally, achieves peak and tough serum levels of about 2 Ag/ml and 0.05 Ag/ml, respectively, with a serum half-life of 10 hr. It is concentrated z 100-fold within phagocytes and about ﬁve-fold in the epithelial lining ﬂuid of the alveoli. Oxazolidinones Linezolid, a member of a new class of synthetic antimicrobial agents, the oxazolidinones, has been approved by the FDA for therapy of respiratory tract infection. Because of its unique mechanism of action, cross-resistance with other antimicrobial agents does not occur. Linezolid has been found to be active against Fusobacterium spp., Prevotella spp., Porphyromonas spp., Bacteroides spp., and peptostreptococci at MIC of V Ag/mL [30] in addition to facultative respiratory pathogens. Linezolid is given in doses of 600 mg I.V. or orally every 12 hr. Its peak and trough serum levels are 12 and 4 Ag/ mL, and its serum half-life is about 4 hr. Doses do not have to be changed for renal failure. Side eﬀects have been minimal, although reversible thrombocytopenia has been reported in about 3% of treated patients when the duration of therapy is greater than 2 weeks. Carbapenems Ertapenem is a new member of the carbapenem family of h-lactam antibiotics. The antimicrobial spectrum of ertapenem is similar to that of imipenem and meropenem, except ertapenem is not active against enterococci, P.

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aeruginosa, and Acinetobacter. Speciﬁcally, ertapenem is active against S. pneumoniae (except highly penicillin-resistant strains), H. inﬂuenzae, obligate anaerobes [31,32] and S. aureus (excluding MRSA). Ertapenem has FDA approval for treatment of community-acquired pneumonia. The approved dose is 1 g every 24 hr for a total duration of therapy of up to 14 days for I.V. administration or 7 days I.M. administration, with an option to switch to an appropriate oral agent after at least 3 days of clinical improvement on ertapenem for a total of 10–14 days of therapy. However, anaerobic lung infection will usually require a longer duration of antibiotic therapy. The dose of ertapenem should be reduced to 500 mg daily if the creatinine clearance is less than 30 mL/min. Duration of Antibiotic Therapy Patients with anaerobic pulmonary infection on eﬀective therapy can be expected to defervesce, and in patients with putrid lung abscess the sputum will become odorless within a week. Chest radiographic ﬁndings may take at least several weeks to resolve. The duration of therapy is controversial. The recommended duration of therapy for aspiration pneumonia is 14 days and for anaerobic lung abscess it is usually at least 4 to 6 weeks to prevent relapse, or until the abscess completely resolves or there is a small, stable residual scar. However, many patients will cease to take medication on their own after several weeks and return at a later point in time for other reasons with a clear chest radiogram. Failure to adequately respond to therapy (persistent fever, worsening of the pulmonary radiographic ﬁndings, or development of empyema) should prompt more intensive investigation to exclude the presence of resistant pathogens, endobronchial obstruction, or a noninfectious etiology. PREVENTION Because the usual pathogenesis of anaerobic pleuropulmonary infection involves aspiration of oral anaerobes, prevention is mainly directed at reducing the risk for aspiration of mouth contents in aspiration-prone patients (i.e., patients with a depressed state of consciousness, gastroesophageal regurgitation, or defective swallowing). Aspiration may be diminished in aspiration-prone patients who require long-term feeding tubes by maintaining them in a semi-recumbent position, by careful monitoring of their gastric volumes, and by use of percutaneous endoscopic gastrostomy or enterostomy tubes rather than naso-enteral feeding tubes. Prudent use of naso-enteral tubes, treatment of seizures, avoiding oversedation, and correction of reversible causes of gastroesophageal reﬂux are other measures to diminish aspiration. Liquids should be thickened in patients having diﬃculty swallowing

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these types of materials. Endobronchial obstruction, which impedes clearance of aspirated material, should be alleviated by removal of foreign bodies and shrinkage of endobronchial neoplasms, if possible. In addition, treatment of periodontal disease can diminish the size of the bacterial inoculum and virulence of the oral ﬂora in aspirated material.

ANCILLARY MANAGEMENT Surgery is rarely indicated for putrid lung abscess, except for the rare complication of massive hemoptysis. Postural and bronchoscopic drainage and chest physiotherapy traditionally have been recommended to enhance antimicrobial therapy. However, caution should be exercised to avoid sudden massive emptying of pus-ﬁlled cavities into the airways and previously uninvolved bronchopulmonary segments. Surgery for actinomycosis may be indicated for resection of necrotic soft tissue and bone and excision of sinus tracts. Anaerobic empyema will require complete drainage, usually by insertion of a chest tube, although thoracotomy and rib resection may be necessary to break loculations to accomplish this.

CONCLUSION Obligate anaerobes are the predominant constituents of normal oropharyngeal ﬂora and produce pleuropulmonary infection in patients who are prone to aspirate. The diagnosis of anaerobic pulmonary infection is frequently presumptive and therapy consequently empirical. Clindamycin has been shown in clinical trials to be more eﬃcacious than penicillin for treatment of anaerobic lung abscess. Use of alternate agents (such as imipenem or meropenem, cefoxitin, h-lactamase/h-lactam antibiotic combinations (e.g., amoxicillin/clavulanate, ampicillin/sulbactam, ticarcillin/clavulanate, or piperacillin/tazobactam), is guided by published studies of their in vitro activity against collected clinical isolates of obligate anaerobic bacteria. Several new drugs (e.g., ertapenem [a carbapenem], new ﬂuoroquinolones, ketolides, and linezolid) that also have in vitro activity against obligate anaerobes have recently become available for the empirical treatment of pneumonia.

REFERENCES 1. Slots J. Sub gingival microﬂora and periodontitis. J Clin Periodont 1979; 6:351– 382. 2. Marina M, Strong CA, Civen R, et al. Bacteriology of anaerobic pleuropulmonary infection. Preliminary Report. Clin Infect Dis 1993; 16(suppl 4):S256– S262.

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3. Levison ME, Bran JL, Ries K. Treatment of anaerobic bacterial infections with clindamycin 2 phosphate. Antimicrob Agents Chemother 1974; 5:276–280. 4. Gonzalez-C CL, Calia FM. Bacteriologic ﬂora of aspiration-induced pulmonary infections. Arch Intern Med 1975; 135:711–714. 5. Lorber B, Swenson RM. Bacteriology of aspiration pneumonia, a prospective study of community and hospital acquired cases. Ann Intern Med 1974; 81: 329. 6. Bartlett JG, O’Keefe P, Tally FP, Louie TJ, Gorbach SL. Bacteriology of hospital-acquired pneumonia. Arch Intern Med 1986; 146:868–871. 7. Bartlett JG, Gorbach SL, Finegold SM. The bacteriology of aspiration pneumonia. Am J Med 1974; 56:202–207. 8. Bartlett JG, Gorbach SL. Treatment of aspiration pneumonia and primary lung abscess: penicillin G vs clindamycin. JAMA 1975; 234:935–937. 9. Pollack HM, Hawkins EL, Bonner JR, et al. Diagnosis of bacterial pulmonary infections with quantitative protected catheter cultures obtained during bronchoscopy. J Clin Microbiol 1983; 17:255–259. 10. Dore P, Robert R, Grolier G, et al. Incidence of anaerobes in ventilator-associated pneumonia with use of a protected specimen brush. Am J Respir Crit Care Med 1996; 153:1292–1298. 11. Mier L, Dreyfuss D, Darchy B, et al. Is penicillin G adequate initial treatment for aspiration pneumonia? A prospective evaluation using a protected specimen brush and quantitative cultures. Intensive Care Med 1993; 19:279–284. 12. Marik PE, Careau P. The role of anaerobes in patients with ventilator-associated pneumonia and aspiration pneumonia, a prospective study. Chest 1999; 115:178– 183. 13. Bartlett JG. Anaerobic bacterial infections of the lung and pleural space. Clin Infect Dis 1993; 16(suppl 4):S248–S255. 14. Jorgensen JH, Ferraro MJ. Antimicrobial susceptibility testing: special needs for fastidious organisms and diﬃcult to detect resistance mechanisms. Clin Infect Dis 2000; 30:799–808. 15. Levison ME, Mangura CT, Lorber B, et al. Clindamycin compared with penicillin for the treatment of anaerobic lung abscess. Ann Intern Med 1983; 98:466– 471. 16. Gudiol F, Manresa F, Pallares R, et al. Clindamycin vs. penicillin for anaerobic lung infections. High rate of penicillin failures associated with penicillinresistant Bacteroides melaninogenicus. Arch Intern Med 1990; 150:2525–2529. 17. Kasten MJ. Clindamycin, metronidazole and chloramphenicol. Mayo Clin Proc 1999; 74:825–833. 18. Falagas ME, Siakavellas E. Bacteroides, Prevotella and Porphyromonas species: a review of antibiotic resistance and therapeutic options. Int J Antimicrob Agents 2000; 15:1–9. 19. Perlino CA. Metronidazole vs clindamycin treatment of anaerobic pulmonary infection: failure of metronidazole therapy. Arch Intern Med 1981; 141:1424– 1427. 20. Smego RA, Foglia G. Actinomycosis. Clin Infect Dis 1998; 26:1255–1261.

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21. Appelbaum PC. Quinolone activity against anaeobes. Drugs 1999; 58:60–64. 22. Schaumann R, Ackerman G, Pless B, et al. In vitro activities of gatifoxacin, two other quinolones, and ﬁve nonquinolone antimicrobials against obligately anaerobic bacteria. Antimicrob Agents Chemother 1999; 43:2783–2786. 23. Goldstein EJ. Review of the in vitro activity of gemiﬂoxacin against grampositive and gram-negative anaerobic pathogens. J Antimicrob Chemother 2000; 45:55–65. 24. Goldstein EJ, Citron DM, Vreni Merriam C, et al. Activities of gemiﬂoxacin (SB 265805, LB 20304) compared to those of other oral antimicrobial agents against unusual anaerobes. Antimicrob Agents Chemother 1999; 43:2726–2730. 25. Goldstein EJ, Citron DM, Merriam CV, et al. Activity of gatiﬂoxacin compared to ﬁve other quinolones versus aerobic and anaerobic isolates from skin and soft tissue samples of human and animal bite wound infections. Antimicrob Agents Chemother 1999; 43:1475–1479. 26. Ackerman G, Schaumann R, Pless B, et al. Comparative activity of moxifoxacin in vitro against obligately anaerobic bacteria. Eur J Clin Microbiol Infect Dis 2000; 19:228–232. 27. Bartlett JG, Dowell SF, Mandell LA, et al. Practice guidelines for the management of community-acquired pneumonia in adults. Clin Infect Dis 2000; 31:347. 28. Heﬀelﬁnger JD, Dowell SF, Jorgensen JH, et al. Management of communityacquired pneumonia in the era of pneumococcal resistance. A report from the drug-resistant Streptococcus pneumoniae therapeutic working group. Arch Intern Med 2000; 160:1400. 29. Goldstein EJ, Citron DM, Merriam CV, et al. Activities of telithromycin (HMR 3647, RU 66647) compared to those of erythromycin, azithromycin, clarithromycin, roxithromycin, and other antimicrobial agents against unusual anaerobes. Antimicrob Agents Chemother 1999; 43:2801–2805. 30. Goldstein EJ, Citron DM, Merriam CV. Linezolid activity compared to those of other selected macrolides and other agents against aerobic and anaerobic pathogens isolated from soft tissues bite infections in humans. Antimicrob Agents Chemother 1999; 43:1469–1474. 31. Goldstein EJ, Citron DM, Merriam CV, et al. Comparative activity of ertapenem and 11 other antimicrobial agents against aerobic and anaerobic pathogens isolated from skin and soft tissue animal and human bite wound infections. J Antimicrob Chemother 2001; 48:641–651. 32. Hoellman DB, Kelly LM, Credito K, et al. In vitro antianaerobic activity of ertapenem (MK-0826) compared to seven other compounds. Antimicrob Agents Chemother 2002; 46:220–224.

16 Treatment of the Common Cold and Viral Bronchitis Harley A. Rotbart University of Colorado Health Science Center Denver, Colorado, U.S.A.

Wealth, honour, freedom, beauty are all his A very king, in short, of kings he is; In wind and limb sound, vigourous, and bold Except when troubled by a wretched cold. —Horace The ancient poet aptly dispels the notion that the syndrome we know as the ‘‘cold’’ is common or trivial—indeed, ‘‘wretched cold’’ is a more appropriate name for this scourge of mankind. The common cold is responsible for 25 million days of missed work, 23 million days of missed school, and 84 million physician visits each year in the United States alone [1]. The common cold is also the most frequent cause of inappropriate antibiotic use in the United States [2,3]. Similarly, acute bronchitis is diagnosed millions of times each year in this country and is responsible for almost 30% of all antibiotic prescriptions—this despite the fact that the vast majority of cases, as with the common cold, are viral in origin [4]. Hence, the appropriate diagnosis and treatment of these two viral syndromes has important health implications for infected individuals as well as for society as a whole. 321

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ETIOLOGY AND EPIDEMIOLOGY The common respiratory viruses are responsible for the vast majority of cases of the common cold and acute bronchitis. Among these pathogens, the picornaviruses—rhinoviruses (RVs) and enteroviruses (EVs)—account for between 50 and 80% of all cases of the common cold [5,6]; inﬂuenza, adenoviruses, and picornaviruses are the leading causes of acute bronchitis [4]. The comparative roles of a variety of pathogens in the common cold and acute bronchitis syndromes are shown in Table 1. The seasonalities of the common cold and acute bronchitis parallel the seasonalities of the major pathogens involved. Incidence of the common cold peaks in the late summer and fall each year with a smaller peak in the spring— both coincident with the seasonal variations of RV and EV infections [1]. In contrast, the winter ‘‘ﬂu season’’ is also the season for acute bronchitic episodes dominated by inﬂuenza and adenovirus infections. PATHOGENESIS The pathogenesis of the common cold is incompletely understood. In persons lacking speciﬁc immunity to the infecting serotype, most exposures result in infection. Symptoms may begin within 12 hr of infection [7]. Transmission appears to be via hand-nose or hand-eye contact following contamination of the hand with nasal secretions from an infected index case. The initial event in cold production is viral infection of the nasal epithelium; the number of productively infected cells appears to be small [8,9] and nasal biopsy studies show little mucosal damage [10]. Elaboration of host inﬂammatory cytokines in response to viral infection is central in the pathogenesis of symptoms and in inducing immune responses. Respiratory epithelial cytokine production likely

TABLE 1 Major Pathogens of the Common Cold and Acute Bronchitis Common cold Picornaviruses Rhinoviruses Enteroviruses Coronaviruses Adenoviruses Respiratory syncytial virus Influenza viruses Parainfluenza viruses

Acute bronchitis Influenza viruses Picornaviruses Rhinoviruses Enteroviruses Adenoviruses Mycoplasma pneumoniae Chlamydia pneumoniae Bordetella pertussis

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contributes to airway hyperreactivity and to an inﬂux of neutrophils in both nasal mucosa and secretions [11]. Cold symptoms also appear to be due to neurologic reﬂexes triggered by the infection [12]. Human HRV has been assumed to be restricted to the upper respiratory tract, but limited evidence indicates that the virus sometimes replicates in the tracheobronchial tree and lung [13,14]. The issue of viral invasiveness of the lower airways also plagues our understanding of acute bronchitis. Inﬂuenza viruses are known for their ability to invade the lower respiratory tract, whereas other etiologic agents of bronchitis (such as picornaviruses and coronaviruses, as noted above) are typically not. Hence, inﬂammatory mediators may be more important in the pathogenesis of bronchitis due to the viruses that are more restricted in their distribution within the respiratory tract. Destruction of the epithelial lining cells of the airways is typical of inﬂuenza bronchitis, but mucociliary dysfunction is probably more important for the virulence of non-inﬂuenzal pathogens. A component of bronchospasm in the pathogenesis of bronchitis has been suspected based on the increased incidence of asthma in patients with histories of bronchitis and, conversely, patients with histories of asthma appear to have increased likelihood of developing bronchitis episodes. Confounding this interpretation are recent data suggesting the presence of rhinoviruses in the lower airways detected by sensitive PCR techniques [14]. What role direct infection by these viruses has in acute viral bronchitis remains to be determined. CLINICAL MANIFESTATIONS Cough is a common clinical hallmark of both the common cold and acute bronchitis. In the former, cough is one of many concurrent symptoms, usually shadowed by nasal complaints, whereas in patients with bronchitis, cough becomes the major problem. The usual incubation period of viral colds is 1 to 3 days. Rhinorrhea, nasal stuﬃness, and sneezing are the commonest symptoms; other typical manifestations include sore or scratchy throat, facial pressure, headache, cough, hoarseness, and less often, malaise, chills, or feverishness [15]. Sore throat tends to be the ﬁrst symptom and runny nose the most bothersome [16]. Signiﬁcant fever is very uncommon in adults and should suggest an alternative diagnosis. Infants and young children have fever more often and may show only mucous nasal discharge. Red, sometimes macerated nostrils, and glassy nasal mucosa are also typically present but examination is primarily useful for excluding other diagnoses. In adults, nasal symptoms usually peak on the second or third day and then gradually subside. Cough usually persists until the end of the ﬁrst week but may be protracted in smokers. The median

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duration of viral colds is one week, but up to one-quarter last 2 weeks or longer [16]. In patients with acute bronchitis, cough is the predominant symptom, but early in the course of the illness other symptoms typically associated with the common cold may also be present. The infection appears to ‘‘settle’’ in the lower respiratory tract, where it may result in sputum production, chest pain, rhonchi, rales, wheezing, and so forth. The patient may present for medical attention only after 1–2 weeks of ‘‘ﬁghting a cold.’’ The cough may last upwards of a month. Fever is more commonly seen in patients with inﬂuenza and adenovirus-associated bronchitis, less often in rhinovirus and coronavirus bronchitis. By deﬁnition, alveolar involvement, changes of pulmonary consolidation, and cyanosis are not classiﬁed as signs of bronchitis but instead imply pulmonary disease. The common cold becomes even more the ‘‘wretched cold’’ when associated with any one of a number of frequently encountered upper and lower respiratory tract complications in both children and adults. Viral respiratory tract infections are the most important predisposing factor to acute otitis media (AOM). Viruses have been detected by culture or antigen assay in 11–41% of middle ear ﬂuids from children with AOM [17,18], with rhinoviruses in up to 8% of such ﬂuids. By polymerase chain reaction, rhinovirus infection is detectable in 35% of children with AOM, including the presence of rhinoviral RNA in 24% of middle ear ﬂuids [19]. In adults, middle ear pressure abnormalities commonly develop during colds [20,21]. Coinfection with viruses and bacteria has been reported to predispose to failure of antibiotic therapy in AOM [22]. Most cases of acute sinusitis thought to result from bacterial disease are secondary to a preceding viral upper respiratory tract infection. Sinus abnormalities are frequently detectable during uncomplicated colds [23]. Consequently, distinguishing a primary viral rhinosinusitis from a secondary bacterial sinusitis is clinically diﬃcult. Rhinovirus is detectable by culture or PCR in 40% of sinus brushings from patients with acute community-acquired sinusitis [24]. Respiratory virus infections are major factors in the induction of acute exacerbations of asthma in adults [25] and in children [26]. In a 2-year study of adult asthmatics 19–46 years of age, peak expiratory ﬂow rate deteriorations occurred during 27% of respiratory illness episodes, and colds were associated with 71% of documented exacerbations [25]. Rhinoviruses are the most commonly identiﬁed pathogens found in asthma exacerbations and hospitalizations for those older than 2 years [27]. Respiratory virus infections are also associated with lower respiratory tract syndromes in other patient populations. Chronic obstructive pulmonary

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disease (COPD) is the second most common chronic, noncommunicable disease in the world [28]. Exacerbations of COPD can be shown to be due to respiratory viruses in more than 25% of all cases, with picornaviruses the leading cause [29]. Hospitalizations due to COPD exacerbations are even more strongly linked to viral infections, with as many as 45% of all such events proved to be triggered by viral infections [29]. Similarly, in children with cystic ﬁbrosis, picornaviruses have been detected in more than 25% of exacerbations, and colds were associated with deterioration in pulmonary function testing [30]. Among adults 60–90 years of age residing in the community, rhinovirus infection was associated with lower respiratory tract symptoms in 65%; 40% consulted their doctor, and 76% of these received antibiotics [31]. The impact of rhinoviruses in elderly people, as measured by those indices, approaches that of inﬂuenza [31]. Up to 40% of exacerbations in patients with chronic bronchitis may be associated with RV infections [32]. In infants younger than 12 months, rhinovirus infections have been associated with hospitalization for lower respiratory tract illness, particularly bronchiolitis [33], and deterioration in those with bronchopulmonary dysplasia [34]. DIAGNOSIS No rapid antigen detection or practical serologic tests exist for rhinovirus infections because of the multiplicity of serotypes. Viral culture takes 3–7 days and is of limited clinical use. PCR detection of RV RNA has been frequently positive in RV culture–negative samples [35] but currently is only a research tool. Diagnosis of inﬂuenza virus infection is possible using traditional culture techniques as well as a variety of rapid antigen assays that are commercially available. Similarly, respiratory syncytial virus infection is diagnosable by both culture and antigen assays. The other major viral pathogens of the common cold and of acute bronchitis are more diﬃcult to diagnose and, as such, speciﬁc viral diagnostic tests are rarely performed for either of these clinical syndromes. MANAGEMENT Cold treatments are associated with subjectivity and strong placebo eﬀects, so adequate blinding of studies is essential. It is diﬃcult to draw positive or negative conclusions from many of these studies because of small sample sizes, limited micobiological support, and diﬀering outcome measures. Recent examples of interventions shown to be of no real value include intranasal hyperthermia [36], zinc gluconate lozenges [37], and oral Echinacea [38].

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Antivirals A major hurdle to eﬀective antiviral therapy for the cold and bronchitis syndromes is the unclear importance of ongoing viral replication in symptom pathogenesis after illness onset. Clinical trials of antiviral therapies for the cold and bronchitis have been limited to compounds with eﬃcacy against the picornaviruses. There are several steps in the replication cycle of the picornaviruses that are potential targets in antiviral therapy. Cell susceptibility, viral attachment, viral uncoating, viral RNA replication, and viral protein synthesis have all been studied as potential strategic targets of anti-picornaviral compounds (Table 2). The following sections brieﬂy review these targets, the mechanisms of action of anti-picornavirus compounds directed at these targets, and the clinical trials performed to date. Interferon Interferons are potent, selective mediators of cellular changes that induce a number of antiviral, antiproliferative, and immunological eﬀects, all of which collectively aﬀect host cell susceptibility to picornavirus infection [39–47]. The cellular antiviral eﬀects of interferons are mediated through speciﬁc receptorsignal transduction pathways. In conjunction with double-stranded RNA, interferons induce the expression of proteins, some of which mediate an antiviral activity. The best-described pathways are (1) 2V,5V-adenylate synthetase; (2) double-stranded RNA-dependent protein kinase; and (3) the Mx proteins. Through transfection/expression systems, an isoform of the 2V,5Vadenylate synthetase system has been linked to the inhibition of replication of picornaviruses [48]. Clinically, children with acute EV meningitis have signiﬁcant elevations in endogenous interferon levels in the CSF [49,50], which may be important in recovery from the infection. Although alfa interferon itself is a very potent inhibitor of picornavirus infection, additive

TABLE 2 Therapeutic Strategies and Candidate Compounds for Treatment of Picornaviral Infections Target Cell susceptibility Viral attachment and binding to host cells Viral uncoating/capsid function Viral replication Viral protein synthesis

Compound class Interferons Antibodies, soluble ICAM Capsid-function inhibitors Enviroxime-like compounds 3C protease inhibitors

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or synergistic protective eﬀects are seen when used in conjunction with capsidinhibiting compounds [43], nucleoside analogues [46], or gamma interferon [51]. Interferons may also work in conjunction with humoral antibodies and macrophages to eliminate picornavirus infections [40]. Intranasal interferon has been shown to be eﬀective as prophylaxis for RV colds in several studies [52–56]. Additional studies demonstrated signiﬁcant eﬃcacy against naturally acquired RV infections and against contact spread of RVs within family groups after experimental induction of a natural cold [52,57]. Side eﬀects of interferon included nasal irritation and stuﬃness, and mucosal ulceration [52,55]. Administered therapeutically 1 day after experimental RV infection, intranasal interferon had no eﬀect on development of infection or symptoms, but did result in moderate reductions of virus shedding and cold symptoms [58]. Additional studies with low-dose intranasal interferon also demonstrated a lack of eﬃcacy in post-exposure prophylaxis of RV infections in families [59]. Capsid-Inhibiting Compounds Capsid-inhibiting compounds block viral uncoating and/or viral attachment to host cell receptors. The resolved three-dimensional structure of the EVs reveals a ‘‘canyon’’ formed by the junctions of VP1 and VP3. Beneath the canyon lies a ‘‘pore’’ that leads to a hydrophobic pocket into which a variety of diverse hydrophobic compounds can bind (Table 2). Although the compounds integrate into a virus capsid via a number of noncovalent, hydrophobic-type interactions, the aﬃnity is high with constants ranging from 2.0 108 to 2.9 107 M [60]. Enhanced potency of the capsidbinding compounds appears to correlate with increased number of molecules of compound per pocket [60,61], proximity of compound to the opening of the pocket [61], increased hydrophobic energy resulting from ﬁlling a greater proportion of the pocket by the compound [60–62] and absence of bulky amino acid substitutions (mutations) within the pocket structure [63–65]. Several potential mechanisms of action of picornavirus inhibition by compounds that aﬀect the function of the virus capsid have been hypothesized. Filling the hydrophobic pocket results in increased stability of the virus, making the virus more resistant to uncoating. The increased stability of the virus-compound complex is evidenced by the resistance to thermal inactivation [66]. This property can be used as a rapid screen in order to identify molecules with binding avidity; the majority of, but not all, compounds with potent antiviral activity also result in thermal stability. It is also possible that a degree of capsid ﬂexibility may be required for uncoating, and activity of these compounds within the hydrophobic pocket may reduce this necessary ﬂexibility, inducing a more rigid structure. Alternatively, changes in

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the conformation of the canyon ﬂoor as a result of drug activity within the underlying pocket may aﬀect the attachment of the virus to the host cell receptor [44]. It has been shown, however, that such perturbations in the canyon ﬂoor do not absolutely correlate with antiviral potency [61,62]. The capsid-inhibiting compounds vary in their spectrum of activity, perhaps as a result of factors such as pocket ﬁt discussed above. Certain compounds demonstrate both anti-EV and anti-RV activity [67 68]; others are more selective to one picornavirus genus or the other [69]. Trials of the ‘‘R’’ series of capsid-binding compounds have been limited to intranasal administration to patients with RV colds [70–72]. Pirodavir (R77975) and R61837 were eﬃcacious in experimentally induced RV colds when these drugs were administered intranasally before or after infection, but prior to onset of symptoms [71,72]; pirodavir required 6 times daily dosing, with eﬃcacy loss at 3 daily doses [72]. Another series of capsid-binding compounds, the phenoxyl imidazoles, are broad-spectrum inhibitors of the EVs and demonstrate therapeutic oral eﬃcacy in animal models [69]. This series has limited potency against the RVs, and further development of candidate drugs has been discontinued. The ‘‘WIN’’ series of compounds has been clinically evaluated in both RV and EV infections. The ﬁrst compound of this group to advance to clinical trials was disoxaril (WIN 51711; Fig. 1). Disoxaril was moderately active against RVs in vitro and very active against EVs both in vitro and in vivo [67,73,74]. The appearance of asymptomatic crystalluria in healthy volunteers prevented further clinical study. Shortening of the aliphatic chain from n =7 to n = 5 and adding chloro- groups to the phenyl ring (Fig. 1) resulted in WIN 54954, which had broad, potent anti-RV and anti-EV activity in vitro and in vivo [75], including oral therapeutic eﬃcacy in mice. Clinical eﬃcacy was assessed in two RV (rhinovirus 23 and rhinovirus 39) challenge trials [76] and one EV challenge trial (coxsackievirus A21) [77]. Despite administering the compound prior to infection and achieving serum concentrations above the in vitro minimal inhibitory concentrations, both RV trials failed to show eﬃcacy of WIN 54954 [76]; very low concentrations of the drug were found in nasal wash samples, the site of the experimental infection. In contrast, WIN 54954 signiﬁcantly reduced the number and severity of colds induced by coxsackievirus A21, and also signiﬁcantly reduced nasal mucous discharge, respiratory and systemic symptoms, and viral titer [77]. The overall symptomatic attack rate was reduced from 15/23 patients in the placebo group to 3/27 in the WIN 54954–treated groups (P=0.0001). This study represents the ﬁrst demonstration of oral eﬃcacy of an anti-EV agent; the diﬀerences in results compared with those in the RV studies using the same compound are enigmatic because the MIC for one of the RV serotypes was identical to that of the coxsackievirus A21 strain used. The fact that EV infections are sys-

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temic, usually with a viremic phase, may explain the enhanced EV eﬃcacy of an orally active compound that achieves good blood levels over the eﬀect seen in RV infections, which are limited to the upper airway where drug distribution may have been insuﬃcient. WIN 54954 was not further developed for clinical use because of adverse reactions of ﬂushing and rash, possibly related to concomitant alcohol ingestion by study volunteers. Pleconaril (3-13,5-dimethyl-4- [[3-methyl-5-isoxazoly)propyl]phenyl]5-(triﬂuoromethyl)-1,2,4-oxadiazole) is the ﬁrst of a new generation of metabolically stable capsid function-inhibitors; this compound has been more extensively evaluated in clinical trials than any other anti-picomaviral agent. Pleconaril has demonstrated broad-spectrum and potent anti-EV and antiRV activity and is highly orally bioavailable [78–81]. In a mouse model of multi-organ system infection following intracranial inoculation of EVs, pleconaril, a capsid-inhibitor compound, has been shown to reduce viral titers in all aﬀected organs and to prevent death of the animals [78]. High levels of pleconaril are achieved in the central nervous system and in the nasal epithelium (M. McKinlay, personal communication). Pharmacokinetic studies of pleconaril have been undertaken in adults, children, and neonates [79–81]. In adults, the pharmacokinetics of pleconaril are best characterized as a onecompartment open model with ﬁrst-order absorption [81], indicative of a compound that is readily absorbed into and distributed throughout the water compartment. Concentrations of pleconaril 12 hr after a single oral dose remain 2.5-fold greater than required to inhibit 95% of EVs in vitro. Neonates and older children have similar PK proﬁles [79,80]. Oral bioavailability, in animals and humans, approaches 70%. In a challenge study of coxsackievirus A21 respiratory infection, 33 volunteers were randomized to receive either 400 mg of pleconaril or matching placebo, orally, 14 hr before inoculation with virus [82]. Beginning after inoculation, subjects received 200 mg capsules twice daily for 6 days. Pleconaril had a signiﬁcant beneﬁcial eﬀect on symptom scores, global assessment, fever, and nasal mucus production, with 41% of placebo-treated subjects experiencing moderate colds versus none in the pleconaril-treated group. Peak viral titers, which occurred on the peak day of symptoms, were reduced by greater than 99% in the pleconaril group compared to the placebo group [82]. In a double-blind, placebo-controlled study of 1024 adults with viral respiratory infection during the fall rhinovirus season, patients receiving pleconaril recovered from all cold symptoms and returned to overall wellness (measured via a global assessment score) 3.5 days sooner than patients receiving placebo [83]. Individual symptoms (including nasal congestion, rhinorrhea, and pharyngitis) each resolved 1–2 days sooner in the pleconariltreated patients.

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In two follow-up double-blind, randomized, placebo-controlled studies of rhinoviral respiratory infection in adults involving more than 2000 patients in 200 centers across the United States and Canada, beneﬁt of pleconaril was again demonstrated [84]. Pooled data from the two studies showed statistically signiﬁcant diﬀerences in the median number of days to illness alleviation (approximately 1 day reduction with reduction in severity of symptoms seen within the ﬁrst 24 hr), as well as statistically signiﬁcant reductions in total symptom scores, days of cold medication use, nights of sleep disturbance, and nasal tissue use [84]. In all short-course (5 days) clinical studies of respiratory infections to date [82–84], a very favorable safety proﬁle has been observed with pleconaril. There have been no diﬀerences in serious adverse events between treatment and placebo groups; a slight increase in the incidence of nausea has been seen in pleconaril-treated patients in certain studies and with certain dosing regimens [85]. Although safety data were favorable for pleconaril in these studies using 5-day therapy, longer treatment in other studies resulted in induction of the cyp 3A enzyme, raising the possibility of undesirable drug-drug interactions (M. McKinlay, personal communication). At this time, strategies to explore this safety concern are being investigated before further development of pleconaril is undertaken. Enviroxime-Related Compounds Enviroxime [2-amino-l-(isopropyisulfonyl)-6-benzimidazole phenyl ketone oxime is a prototype compound for a series of molecules with broad antiEV and anti-RV activity [86–88]. The mechanism of action of these compounds has been suggested to be the inhibition of RNA replication via targeting the 3A protein coding region of the viruses [89]. The drugs apparently prevent formation of the RNA replicative intermediate, a complex dependent on both viral proteins 3A and 3AB [89], and, hence, the formation of new plus-strand RNA molecules. Vinyl acetylene benzimidazoles derivatives of enviroxime provide improved bioavailability of the compounds; ﬂuoridation of these latter structures further enhances blood levels in animal models [90,91]. This class of compounds can be added to tissue culture systems several hours after viral inoculation without loss of antiviral activity, again reﬂecting their action at a later stage of the viral life cycle (i.e., RNA replication). Enviroxime resulted in modest clinical and virologic beneﬁt in some studies [92,93] and no beneﬁt in others [94,95]. Problems with poor pharmacokinetics and undesirable toxicology and side eﬀects resulted in discontinuance of that program. Newer derivatives of enviroxime promise better bioavailability and tolerance but have not been clinically evaluated.

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Soluble ICAM The majority of rhinoviruses bind to the intracellular adhesion molecule (ICAM) receptor on cell surfaces. A strategy to bind infecting virus with an intranasally applied soluble form of ICAM, named tremacamra, resulted in modest clinical beneﬁts in a volunteer study with challenge infection. Statistically signiﬁcant reductions in total symptom score, proportion of clinical colds, and nasal mucus weight were achieved [96]. Further development of this compound has not been undertaken as of this time. 3-C Protease Inhibitors A series of compounds are under development that target the 3C protease of picornaviruses, resulting in inhibition of viral protein synthesis via blocking viral speciﬁc protein processing [97]. Published results are limited to those with tripeptide aldehydes derived from the sequence of a natural 3C cleavage site, Leu-Phe-Gln. Anti-enzyme activity is potent (Kl = 6 nM) with high therapeutic indices in vitro. Like the RNA inhibitors discussed above, time of addition with the protease inhibitors is several hours without loss of antiviral activity. These compounds appear to have both anti-RV activity and anti-EV activity and appear to have an antiviral eﬀect even if initiated (in the animal model) several hours after infection. Clinical trials in RV upper respiratory infections for the lead compound, AG7088, have been discontinued as of this time in an attempt to improve characteristics of the formulation. Ancillary Management Symptomatic Therapies Antihistamines have been frequently used for the treatment of common colds but their usefulness has been the subject of controversy [98]. Only ﬁrstgeneration antihistamines (e.g. chlorpheniramine, clemastine), which have anticholinergic and sedating eﬀects, are useful in treating cold-associated rhinorrhea and sneezing [99,100]. Selective, nonsedating ﬁrst-generation antihistamines (e.g., terfenadine, loratadine) are ineﬀective [101]. The anticholinergic nasal spray ipratropium bromide has been shown to reduce rhinorrhea by 30% in natural colds [102]. Corticosteroids do not provide clinically meaningful beneﬁt in RV colds and may serve to increase viral replication [103]. Inhaled steroids, although used by many practitioners in treating bronchitis, have also not been proven to be beneﬁcial [4]. Nonsteroidal antiinﬂammatory agents variably beneﬁt cold symptoms but certain ones (e.g., ibuprofen, naproxen) relieve discomfort and systemic symptoms [104]. These

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latter compounds do suppress cough. Both naproxen and ibuprofen have been shown in clinical trials to be active cough suppressants [4,105]. Expectorants have not been adequately studied in colds or viral bronchitis. Antibiotics Despite the frequent use of antibiotics during colds, no convincing evidence of beneﬁt exists for their use. A recent meta-analysis [106] found that antibiotic treatment in over 1500 children did not aﬀect the symptoms of common cold. A subset of about 20% of cold suﬀerers are colonized with pathogenic respiratory bacteria (S. pneumoniae, H. inﬂuenzae, M. catarrhalis) and may experience modest symptom beneﬁt and lower rates of subsequent antibiotic use if treated with amoxicillin-clavulanate [107]. Noncolonized patients do not beneﬁt, and gastrointestinal (GI) intolerance develops ﬁve-fold more often in amoxicillin-clavulanate recipients [107]. Determination of carriers of pathogenic bacteria is not practical in the oﬃce setting and of doubtful clinical value. Antibiotics should be withheld unless secondary bacterial infections are strongly suspected. Alternative Therapies A wide variety of alternative therapies have been tried over the past many years in attempts to alleviate the symptoms of the cold and bronchitis. Zinc lozenges have been subjected to numerous randomized clinical trials [37,108– 110]. Although certain studies have shown modest eﬀects in treating colds, the collective data from all studies show little beneﬁt [37,108–110]. Even in those individual studies with positive results, undesirable side eﬀects such as burning, tingling, bad taste, and nausea limit the utility of this treatment [109]. A zinc nasal gel has been studied in a single randomized clinical trial with highly positive results reported [111]. Study design ﬂaws, including no standardized duration of therapy or monitoring of concomitant treatments, require conﬁrmation of beneﬁcial results with additional studies before this intervention can be recommended. Limited randomized clinical trials with echinacea have found no beneﬁt [38]. Finally, high-dose vitamin C has been studied more than 20 times in randomized, controlled clinical trials for prevention and/or treatment of the common cold. When analyzed collectively, there is no apparent reduction in the incidence of colds when vitamin C is used prophylactically. However, the combined variables of duration and severity of the cold are improved by treatment with onset of cold symptoms. Among all studies, this reduction was of the order of magnitude of 23%, but in the largest and best controlled of the studies, it appears that duration and/ or severity are reduced by up to 10% with vitamin C treatment [112].

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74. McKinlay MA, Steinberg BA. Oral eﬃcacy of WIN 51711 in mice infected with human poliovirus. Antimicrob Agents Chemother 1986; 29:30–32. 75. Woods MG, Diana GD, Rogge MC, Otto MJ, Dutko FJ, McKinlay MA. In vitro and in vivo activities of WIN 54954, a new broad-spectrum antipicornavirus drug. Antimicrob Agents Chemother 1989; 33:2069–2074. 76. Turner RB, Dutko FJ, Goldstein NH, Lockwood G, Hayden FG. Eﬃcacy of oral WIN 54954 for prophylaxis of experimental rhinovirus infection. Antimicrob Agents Chemother 1993; 37:297–300. 77. Schiﬀ GM, Sherwood JR, Young EC, Mason LJ. Prophylactic eﬃcacy of WIN 54954 in prevention of experimental human coxsackievirus A21 infection and illness. Antiviral Res 1992; 17(suppl):92. 78. Pevear DC, Tull TM, Seipel ME, Groarke JM. Activity of pleconaril against enteroviruses. Antimicrob Agents Chemother 1999; 43:2109–2115. 79. Kearns GL, Bradley JS, Jacobs RF, et al. Pleconaril pharmocokinetics in neonates. Abstracts of the 36th annual Infectious Diseases Society of America meeting, Denver, CO, 1998. Abstract 750. 80. Kearns GL, Abdel-Rahman SM, James LP, et al. Single-dose pharmacokinetics of a pleconaril oral solution in children and adolescents. Antimicrob Agents Chemother 1999; 43:634–638. 81. Abdel-Rahman SM, Kearns GL. Single oral dose escalation pharmacokinetics of pleconaril capsules in adults. J Clin Pharmacol 1999; 39:613–618. 82. Schiﬀ GM, McKinlay MA, Sherwood JR. Oral eﬃcacy of VP63843 in coxsackievirus A21 infected volunteers. Abstracts of the 36th Interscience Conference on Antimicrobial Agents and Chemotherapy, New Orleans, LA, 1996. Abstract H-43. 83. Hayden FG, Hassmann HA, Coats T, et al. Pleconaril treatment shortens duration of picornavirus respiratory illness in adults. Abstracts of the 39th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, CA, 1999. Abstract. 84. Hayden FG, Kim K, Hudson S. Pleconaril treatment reduces duration and severity of viral respiratory infection (common cold) due to picornaviruses. Abstracts of the 41st Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, IL, 2001. Abstract. 85. Rotbart HA, Liu S. Pleconaril safety—cumulative study data for a novel antiviral compound. Abstracts of the 39th Annual Meeting of the Infectious Diseases Society of America, San Francisco, CA, 2001. Abstract. 86. DeLong DC, Nelson JD, Wu E, Warren B, Wikel J, Templeton RJ, Dinner A. Virus inhibition studies with AR -36 III. Relative activity of syn and anti isomers, abstr. 34 In Program and abstracts of the 18th Interscience Conference on Antimicrobial Agents and Chemotherapy. American Society for Microbiology, Washington, DC, 1978a. 87. DeLong DC, Nelson JD, Wu CYE, Warren B, Wikel J, Chamberlin J, Montgomery D, Paget CJ. Virus inhibition studies with AR-336. 1. Tissue culture activity, abstr. S-128, p. 234. In Abstracts of the 78th Annual Meeting of the American Society for Microbiology 1978. American Society for Microbiology, Washington, DC, 1978b.

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88. Wikel JH, Paget CJ, DeLong DC, Nelson JD, Wu CYE, Paschal JW, Dinner A, Templeton RJ, Chaney MO, Jones ND, Chamberlin JW. Synthesis of syn and anti isomers of 6-[(hydroxyimino)phenAmethA[-l-[(l-methyieth@l)sulfonyi]-i H-benzimidazol-2-amine. Inhibitors of rhinovirus multiplication. J Mod Chem 1980; 23:368–372. 89. Heinz BA, Vance LM. The antiviral compound enviroxime targets the 3A coding region of rhinovirus and poliovirus. J Virol 1995; 69:4189–4197. 90. Tebbe MJ, Spitzer WA, Tang J. Oral bioavailability screening of the antirhinoviral vinyl acetylene benzimidazoles. Abstracts of the 10th International Conference on Antiviral Research, Atlanta, GA, 1997:A89. 91. Tebbe MJ, Spitzer WA, Victor S, et al. Antirhinoviral vinyl acetylene benzimidazoles. Abstracts of the 10th International Conference on Antiviral Research, Atlanta, GA, 1997:A75. 92. Philipotts RJ, Wallace J, Tyrrell DAJ, Tagart VB. Therapeutic activity of onviroxime against rhinovirus infection in volunteers. Antimicrob Agents Chemother 1983; 23:671–675. 93. Philipotts RJ, DeLong DC, Wallace J, Jones RW, Reed SE, Tyrrell DAJ. The activity of enviroxime against rhinovirus infection in man. Lancet 1981; 2:1342– 1344. 94. Hayden FG, Gwaltney JM Jr. Prophyiactic activity of intranasal enviroxime against experimentally induced rhinovirus type 39 infection. Antimicrob Agents Chemother 1982; 21:892–897. 95. Miller FD, Monto AS, DeLong DC, Exelby A, Bryan ER, Srivastava S. Controlled trail of enviroxime against natural rhinovirus infections in a community. Antimicrob Agents Chemother 1985; 27:102–106. 96. Turner R, Wecker Mt, Pohl G, et al. Eﬃcacy of tremacamra, a soluble intercellular adhesion molecule 1, for experimental rhinovirus infection; a randomized clinical trial. JAMA 1999; 281:1797–1804. 97. Patick AK, Ford C, Binford S, et al. Evaluation of the antiviral activity and cytotoxicfty of peptide inhibitors of human rhinovirus 3C protease, a novel target for antiviral intervention. Abstracts of the 10th International Conference on Antiviral Research, Atlanta, GA, 1997:A75. 98. Luks D, Anderson MR. Antihistamines and the common cold. A review and critique of the literature. J Gen Intern Med 1996; 11:240–244. 99. Gwaltney JM Jr, Park J, Paul RA, Edelman DA, O’Connor RR, Turner RB. Randomized controlled trial of clemastine fumarate for treatment of experimental rhinovirus colds. Clin Infect Dis 1996; 22:656–662. 100. Turner RB, Sperber SJ, Sorrentino JV, et al. Eﬀectiveness of clemastine fumarate for treatment of rhinorrhea and sneezing associated with the common cold. Clin Infect Dis. In press. 101. Berkowitz RB, Tinkelman DG. Evaluation of oral terfenadine for treatment of the common cold. Am Rev Respir Dis 1987; 136:556–560. 102. Hayden FG, Diamond L, Wood PB, Korts DC, Wecker MT. Eﬀectiveness and safety of intranasal ipratropium bromide in common colds. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 1996; 125:89–97. 103. Gustafson LM, Proud D, Hendley O, Hayden FG, Gwaltney JM. Oral pred-

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Rotbart nisone therapy in experimental rhinovirus infections. J Allergy Clin Immunol 1996; 97:1009–1114. Sperber SJ, Hendley JO, Hayden FG, Riker DK, Sorrentino JV, Gwaltney JM Jr. Eﬀects of naproxen on experimental rhinovirus colds. A randomized, double-blind, controlled trial. Ann Intern Med 1992; 117:37–41. Gwaltney J. clinical and mechanistic perspectives on acute self-limited cough. Symposium Report from the World Congress of Pharmacy and Pharmaceutical Sciences. Int Pharm J 1997; 11:5–7. Gadomski AM. Potential interventions for preventing pneumonia among young children: lack of eﬀect of antibiotic treatment for upper respiratory infections. Pediatr Infect Dis J 1993; 12:115–120. Kaiser L, Lew D, Hirschel B, et al. Eﬀects of antibiotic treatment of the subset of common-cold patients who have bacteria in nasopharyngeal secretions. Lancet 1996; 347:1507–1510. Jackson JL, Lesho E, Peterson C. Zinc and the common cold: a meta-analysis revisited. J Nutr 2000; 130(suppl 5S):1512S–1515S. Marshall S. Zinc gluconate and the common cold. Review of randomized controlled trials. Can Fam Physician 1998; 44:1037–1042. Macknin ML, Piedmonte M, Calendine C, Janosky J, Wald E. Zinc gluconate lozenges for treating the common cold in children: a randomized controlled trial. JAMA 1998; 279:1962–1967. Hirt M, Nobel S, Barron E. Zinc nasal gel for the treatment of common cold symptoms; a double-blind, placebo-controlled trial. ENT Journal 2000; 79: 778–782. Hemila H. Does Vitamin C alleviate the symptoms of the common cold—a review of current evidence. Scand J Infect Dis 1994; 26:1–6. Arruda E, Hayden FG. Clinical studies of antiviral agents for picornaviral infections. In: Jeﬀries DJ, DeCierrq E, eds. Antiviral Chemotherapy. John Wiley & Sons Ltd, 1995.

17 Treatment of Influenza-Related Respiratory Tract Infections Ann L. N. Chapman Royal Hallamshire Hospital Sheffield, England

Martin J. Wood

y

Heartlands Hospital Birmingham, England

INTRODUCTION Inﬂuenza is one of the most widespread infectious diseases throughout the world, infecting many millions of people annually. It is of major importance for two reasons: ﬁrst, its potential to cause massive-scale pandemics with signiﬁcant mortality and major economic sequelae; and second, its preponderance in causing severe viral and secondary bacterial pneumonia, particularly in the elderly, the chronically inﬁrm, and the immunosuppressed. Although vaccination is eﬀective in preventing many cases of inﬂuenza in healthy and high-risk individuals, cases still occur due to incomplete coverage, poor vaccine-induced immunity in some groups, and variant viral strains y Deceased.

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not covered by the vaccine. Antiviral treatment for acute inﬂuenza has been available since the 1960s, but it is only in the past few years, with the development of the neuraminidase inhibitors, that speciﬁc treatment has been considered on a wide scale. In this chapter, we review the current state of knowledge and recommendations for the use of antiviral drugs for acute inﬂuenza, in particular for the respiratory complications.

VIROLOGICAL AND CLINICAL ASPECTS The Virus Inﬂuenza viruses are members of the orthomyxoviridae family. They are 100 nm diameter, spherical or rod-shaped, enveloped, single-stranded RNA (antisense) viruses, with three major subtypes: A, B, and C. Types A and B cause most clinically relevant disease. The virus encodes a number of proteins, including the neuraminidase and hemagglutinin glycoproteins embedded in the envelope; the matrix M1 protein, which forms a layer surrounding the viral nucleocapsid; nucleoproteins that associate closely with viral RNA; and several proteins involved in RNA transcription and processing. Inﬂuenza A also contains a further envelope protein, M2, which is not found in inﬂuenza B and C subtypes [1]. In addition to the A, B, and C subtypes, inﬂuenza viruses are classiﬁed further on the basis of the type of hemagglutinin (H) and neuraminidase (N) glycoproteins present. To date, there are 15 and 9 of these, respectively, and these two proteins are important targets for both antibody and cellmediated immunity. Hemagglutinin is a highly variable glycopeptide that is involved in viral attachment and fusion with cells in the respiratory tract by binding to sialic acid–containing receptors on the cell surface. The neuraminidase is an enzyme that aids the release of newly formed virus from the surface of infected cells. It does this by cleaving terminal sialic acid residues from glycoproteins in the cell membrane. Because the hemagglutinin molecule itself contains sialic acid residues, the neuraminidase enzyme also cleaves these, preventing viral clumping and aiding dissemination. Furthermore, neuraminidase also inhibits virus binding to mucoproteinrich respiratory secretions, allowing the virus to penetrate through the secretions to the surface of neighboring cells and to be transmitted to other individuals. Emerging viral strains are classiﬁed not only on the basis of their core proteins (into A, B, and C subtypes) but also according to their geographic and species origin, year of isolation, and which hemagglutinin and neuraminidase types they possess. Currently there are two major strains of inﬂuenza A circulating: H1N1 and H3N2. The outbreak of avian-associated inﬂuenza in

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1997 in Hong Kong was associated with an H5N1 strain, which did not disseminate widely [2]. Pandemics occur as a result of a process known as antigenic shift, in which a new viral strain emerges with a completely diﬀerent hemagglutinin or neuraminidase type to circulating viruses [3]. This may arise due to recombination of avian and human viruses in an ‘‘intermediate’’ host—for example, a pig—resulting in a recombinant virus radically diﬀerent from the prevailing strains, to which there is little or no human herd immunity. However, in the recent Hong Kong outbreak, it is thought that a viral strain found in domestic birds was able to transfer directly to humans without an intermediate species; this pattern of transmission may lead to explosive outbreaks and pandemics with little warning and is of major concern for the future. Both inﬂuenza A and B have the potential to cause epidemics and pandemics, although B viruses tend to be more genetically stable and result in less severe outbreaks due to higher levels of herd immunity. In addition to this dramatic antigenic shift, a more gradual process of antigenic drift occurs constantly and results in the emergence of new viral strains every few years that resemble their ‘‘parent’’ strains to a varying extent—the degree of homology inﬂuences the level of herd immunity and thus clinical impact. Careful surveillance of such viral changes allows an approximate prediction to be made regarding which viral strains are likely to predominate during the coming year, enabling vaccination for at-risk groups [4]. Epidemiology During most winters, an outbreak of inﬂuenza infection, lasting a few weeks, spreads rapidly throughout the population. The outbreaks vary in intensity but in an average year inﬂuenza is estimated to be responsible for from 18 to 20 million respiratory illnesses in the United States: 13.8 to 16.0 million of these are in individuals younger than 20 years and 4.1 to 4.5 million in persons 20 years of age or older [5]. In addition, complications of acute inﬂuenza are common, with 150,000 hospitalizations and 10–40,000 deaths yearly in the United States [6,7]. Most morbidity is seen in the largest proportion of the population (i.e., schoolchildren and healthy adults). The highest rates of morbidity and mortality, however, occur in persons over 65 years of age. In the United States alone, inﬂuenza virus infection results annually in 25 million visits to physicians and millions of days of work lost and costs the nation an estimated 12 billion [8,9]. As mentioned above, inﬂuenza viruses have the potential to cause massive pandemics, aﬀecting up to 50% of the community with major associated morbidity and mortality [10,11] as a result of a genetic shift. There were

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three major pandemics in the twentieth century: the 1918 ‘‘Spanish ﬂu’’ killed an estimated 20 million people worldwide and the pandemics of 1957 and 1968 each led to more than 100,000 deaths in the United States alone [12]. The recent outbreak of an H5N1 avian inﬂuenza virus A in Hong Kong [2] should serve as a warning that a further pandemic (probably in the near future) is inevitable and must be planned for [13,14]. Viral Pathogenesis Inﬂuenza virus is predominantly spread via inhalation of small particle aerosols (<10 Am diameter) produced by sneezing, coughing, or even talking. It is highly transmissible, with an attack rate of up to 50% in epidemics, and stable for prolonged periods at a range of temperatures and humidities. The virus replicates only in the epithelial cells of the upper and lower respiratory tract. Cell death occurs as a result of necrosis and also, it is thought, apoptosis, with release of virions and infection of neighboring epithelial cells. Thus infection tends to spread along epithelial surfaces rather than occurring at discrete sites. Histologically, the respiratory epithelium shows edema, hyperemia, and superﬁcial ulceration. As the infection spreads distally, the histological changes become more severe, with necrotizing tracheobronchitis, ulceration, and sloughing of the mucosa, and a hemorrhagic pneumonia with hyaline membrane formation. Secondary bacterial pneumonia may occur, with a neutrophilic inﬁltrate. Clinical Features Inﬂuenza is an acute respiratory tract infection aﬀecting all ages. In its typical form, occurring in adolescents and young adults, it generally presents after a short incubation period of 1 to 3 days, with abrupt onset of fever (usually above 38jC) and chills, headache, dry cough, myalgia, and prostration. The patient may have sore throat, sneezing, and nasal discharge, but local symptoms tend to be less marked than systemic ones. Children seem more prone to having gastrointestinal symptoms, such as vomiting and abdominal pain, in addition. A typical case is associated with 5 to 6 days of limited activity, 3 to 4 days of bed rest, and about 3 days of lost school or work [15]. Convalescence occurs over the ensuing 1 to 2 weeks, although some individuals may experience prolonged cough and wheeze due to increased bronchial reactivity. Inﬂuenza A and B subtypes tend to produce similar illnesses, whereas type C results in a milder infection with fewer systemic symptoms and complications. Many infections with any of the viral strains are asymptomatic.

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In the very young and very old this typical picture may not be seen. In the elderly, there may be fever and confusion without symptoms or signs localizing infection to the respiratory tract and presenting a diagnostic challenge. Some patients may present with deterioration in their chronic pulmonary disease or congestive cardiac failure. Infants may also develop fever, vomiting, and convulsions without localizing features, or may show clinical evidence of respiratory tract involvement with laryngotracheobronchitis or pneumonia. Although most infections occur in school-age children and young adults, it is the very young and very old who are most at risk of developing severe inﬂuenza and its complications [16–18]. These are more likely in the presence of chronic ill health: in young children, predisposing conditions include congenital heart disease, cystic ﬁbrosis, asthma, sickle cell disease and neoplasm; in the older age group, chronic cardiovascular, respiratory and renal disease, diabetes mellitus, and immunosuppression increase the risk of complications and death. Inﬂuenza pneumonia occurs uncommonly and mainly in the context of major inﬂuenza A epidemics. In the 1918–1919 pandemic, primary viral pneumonia was a major cause of death in young adults, particularly pregnant women. Subsequent work has shown that pregnancy is an independent risk factor for severe or complicated infection, the risk increasing as pregnancy progresses [19]. The illness starts with a typical pattern but progresses rapidly to fever, cough, dyspnea and hypoxia. The chest radiograph may show an interstitial pattern of shadowing, and examination of sputum yields no bacteria (initially) on microscopy or culture, but a positive viral culture. Inﬂuenza pneumonia has a high mortality and survivors may develop residual diﬀuse pulmonary ﬁbrosis. The more frequent respiratory complications of inﬂuenza, particularly in the elderly and in patients with a predisposing factor, are secondary bacterial pneumonia and bronchitis [20]. Such patients may have a typical pattern of infection, initially appearing to improve over a period of 1 to 2 weeks, but then become more unwell, with fever and productive cough. Secondary bacterial pneumonias are the major cause of death in nonpandemic inﬂuenza and are thought to occur because of local changes in the respiratory mucosa: impaired mucociliary clearance of secretions, increased amounts of extravascated tissue ﬂuid providing a rich growth medium for bacteria, and altered adherence of bacteria to the respiratory epithelium. Local pro-inﬂammatory cytokines such as interleukins 6 and 8 and tumor necrosis factor–a may also play a role [21]. Streptococcus pneumoniae and Haemophilus inﬂuenzae are the main associated pathogens; the widespread introduction of pneumococcal vaccination for individuals with chronic ill health or immunosuppression may paradoxically reduce inﬂuenza

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mortality. Staphylococcus aureus pneumonia is less common but carries a high mortality. In children, otitis media is a common complication [22]. Less common complications of inﬂuenza include encephalopathy and encephalitis, Reye’s syndrome, Guillain-Barre´ syndrome, and myocarditis. ANTIVIRAL AGENTS There are four licensed anti-inﬂuenza agents available in the United States and Europe. Adamantanes Amantadine and rimantadine are drugs known as adamantanes that were recognized in the 1960s as having activity at concentrations below 1Ag/mL against inﬂuenza A but not inﬂuenza B viruses [23]. During the initial stages of replication of inﬂuenza A viruses, the M1 protein needs to be dissociated from the ribonucleoprotein complexes before the latter can enter the cell nucleus and commence replication. This requires an acid milieu, and the M2 protein, which spans the viral membrane, acts as an ion channel through which hydrogen ions reach the center of the viral particle and facilitate the M1 protein/ ribonucleoprotein dissociation [24]. Amantadine and rimantadine act by binding to the M2 ion channel and blocking its function, thus indirectly preventing the initiation of viral replication [25]. Amantadine was approved for chemoprophylaxis of inﬂuenza A in 1966 and in 1976 for treatment of inﬂuenza A virus infections in persons older than 1 year. Rimantadine was approved in the United States in 1993 for treatment and chemoprophylaxis of inﬂuenza A in adults but only for prophylaxis among children (Table 1). Both agents are almost completely absorbed after oral dosing, amantadine about twice as rapidly than rimantadine, and both are excreted in urine. The half-life of amantadine is about 15 hr in younger adults but twice as long in elderly individuals. Rimantadine has a half-life that is about 30 hr in all age groups [26]. Both amantadine and rimantadine are eﬀective in reducing the intensity and duration of symptoms of inﬂuenza A if started within 2 days of onset of symptoms [27,28]. They appear to have similar eﬃcacy, in general reducing the duration of illness by one day [29]. By preventing viral replication, they also reduce the amount of free virus in respiratory secretions and may therefore be of beneﬁt in reducing transmission in an epidemic situation. Amantadine and rimantadine are administered orally once or twice daily. The daily dose of either drug is 200 mg (100 mg in the elderly or those with renal impairment and 5 mg/kg body weight, to a maximum of 150 mg, in children from 1 to 9 years of age). The most prominent side eﬀects of aman-

Oral (tablets or syrup)

Inhalation

Oral (capsules or powder for oral suspension)

Rimantadine

Zanamivir

Oseltamivir

Prophylaxis z 13 years

Prophylaxis not approved Treatment z 1 year

Treatment z 7 years

Prophylaxis z 1 year

75 mg once daily

75 mg twice dailyc

daily

dailyb

dailyb

dailyb

100 mg twice 100 mg twice 100 mg twice 10 mg twice N/A

Prophylaxis z 1 year Treatment z 18 years

100 mg twice dailyb

Dose—adultsa

Treatment z 1 year

Age range approved for treatment/prophylaxis

Duration of treatment usually 5 days; prophylaxis for 7 days or until end of outbreak. N/A not approved. b Reduce dose to 100 mg daily in elderly patients and patients with renal impairment. c Reduce dose for patients with serum creatinine clearance of <30 mL/min.

a

Oral (tablets or syrup)

Route

Antiviral Agents for Inﬂuenza

Amantadine

Drug

TABLE 1

N/A

See package insert

N/A

N/A

As amantadine

N/A

<40 kg 5 mg/kg (to max 150 mg daily) >40 kg 100 mg twice daily (treatment and prophylaxis)

Dose—childrena

Nausea and vomiting

Bronchospasm (uncommon)

Nausea and vomiting, diarrhea

Confusion, anxiety, impaired concentration, seizures, nightmares, hallucinations; nausea and vomiting

Side effects

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tadine are neuropsychological, since this agent promotes release of catecholamines [30]. Symptoms include anxiety, impaired concentration, depression, and insomnia; these occur in 10–20% of patients, probably more commonly in the elderly [31,32]. Side eﬀects are related to the serum concentration and where levels are high—for example, in individuals with renal impairment— include hallucinations or seizures. Even with normal therapeutic serum levels, amantadine may induce ﬁts in those with a predisposition, and thus the drug is contraindicated in patients with epilepsy. Rimantadine does not induce catecholamine release in the same way, and side eﬀects are much less common and usually gastrointestinal in nature [33]. Rimantadine is the drug of choice when available because of its improved side-eﬀect proﬁle. The main concern with these agents is the rapid development of resistance during a course of therapy. This occurs in between one-quarter and onethird of individuals taking either of these agents. The molecular basis of resistance is a point mutation at residue 26, 27, 30, 31, or 34 in the gene encoding the M2 protein, and development of resistance to one agent confers resistance to the other in this group [34]. The resistant strains can be transmitted to other persons and illnesses caused by resistant strains are indistinguishable from those caused by amantadine-susceptible strains[35–37]. Resistant virus may become the predominant viral type in an outbreak or epidemic, and may limit use of this group of antiviral agents for treatment or prevention of new infections [38]. However, although resistance emerges rapidly during treatment, natural resistance is uncommon and long-term resistance is unlikely because of the emergence of new drug-sensitive strains every few years by antigenic drift [39]. Neuraminidase Inhibitors The neuraminidase enzyme is essential for the replication of inﬂuenza A and B viruses (see above). Studies have now shown that although most of the protein varies between strains, the amino acid residues that line the active site and interact with the sialic acid substrate are highly conserved in all strains that have been studied [40,41]. This ﬁnding suggested that competitive inhibitors that mimicked sialic acid might inhibit neuraminidase and hence have activity against a wide range of strains of inﬂuenza A and B [42]. To date, two such agents have been developed: zanamivir and oseltamivir. Both are analogues of N-acetylneuraminic acid, the cell-surface receptor for inﬂuenza viruses and potently inhibit inﬂuenza virus neuraminidase activity at low nanomolar concentrations [43]. Resistance to the neuraminidase inhibitors may develop either as a result of mutations altering the binding of the drug to the neuraminidase enzyme or due to a reduction in the aﬃnity of the hemagglutinin-receptor

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binding so that there is less need for neuraminidase activity to enable virus to be released from infected cells [44]. Resistant strains appear only after several days of treatment; their emergence does not alter the time course of the illness. Studies in animals have suggested that resistant strains are less virulent [44]. Zanamivir The ﬁrst analogue of N-acetylneuraminic acid to be developed in 1969 was 2deoxy-3,3-dihydro-N-acetyl neuraminic acid (also known as Neu5Acen), but this was found to be insuﬃciently speciﬁc for viral neuraminidase. Once the crystal structure of the viral enzyme was determined [40], then the aﬃnity of compounds for the active site could be enhanced and this led to 4-guanido Neu5Acen (GG167 or zanamivir) [45,46]. Zanamivir is licensed for the treatment of inﬂuenza A and B infections in adults and adolescents of 12 years and older (Table 1). It has low oral bioavailability and needs to be administered by inhalation through the mouth or nose. In volunteers, scintigraphic studies have demonstrated that nearly 80% of a dose of zanamivir inhaled through the mouth is deposited in the oropharynx, and that only 15% or so reaches the tracheobronchial and pulmonary sites of viral replication [47]. About 10–20% of the inhaled dose is absorbed and then excreted unchanged in the urine [48]. The clinical eﬃcacy of zanamivir given by intranasal administration was initially demonstrated in experimental inﬂuenza A (H1N1) infection of volunteers [49]. When given before experimental infection, zanamivir dosages of 3.6–16 mg, given two to six times daily, prevented 82% of labora-tory-proven infection and 95% of febrile illnesses, compared with placebo (P<0.001). Early treatment of experimental infection reduced peak viral titers, duration of viral shedding, and the duration of illness compared with placebo [49]. Clinical studies of zanamivir have shown that inhaled zanamivir (10 mg twice daily for 5 days), given with or without concomitant intranasal zanamivir within 48 hours of natural inﬂuenza A or B infection, signiﬁcantly shortens the duration of symptoms compared with placebo, on average by 1 to 11⁄2 days [50,51]. Complications and antibiotic use for secondary bacterial infections were also reduced in previously healthy individuals [52] and this effect is also likely to occur in high-risk patients [51], although the number of such patients studied to date has been too small to give conclusive information. No signiﬁcant diﬀerences in side eﬀects between placebo and zanamivir were reported in these trials. However, zanamivir can cause bronchospasm and airﬂow reduction and hence may need to be used with caution in patients with chronic respiratory disease: in one study of 11 patients with mild to moderate asthma, however, there was no reduction in pulmonary function or airway hyperreactivity to methacholine [53]. Despite this, the manufacturers

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recommend that patients on maintenance bronchodilator therapy use their brochodilator before taking zanamivir. Zanamivir in a dose of 10 mg once daily was 30% eﬀective in the prevention of infection and 67% eﬀective in prevention of illness when given before exposure during a community epidemic [54]. In a family study, when zanamivir was given to family members 5 years of age or older who had been exposed to an index case, new cases were prevented in 79% of persons [55]. Resistance mutations were not detected in the trials of zanamivir but mutations in both the hemagglutinin and neuraminidase genes occurred in an immunocompromised patient treated with zanamivir for 2 weeks for an inﬂuenza B infection [56]. Oseltamivir Incorporation of a carbocyclic structure into the neuraminidase inhibitor molecule improved the stability and activity of the compounds and led to the development of Ro640802 (oseltamivir carboxylate) [57]. Oseltamivir carboxylate is another potent and speciﬁc inﬂuenza neuraminidase inhibitor [43]. It is licensed for treatment of inﬂuenza A and B infections in individuals of 1 year and older, and for prophylaxis of patients of 13 years and older (Table 1). Although oseltamivir carboxylate is more lipophilic than zanamivir, its oral bioavailability is similarly low [58] and so an ethyl ester prodrug was developed. This compound, after oral administration as a capsule or liquid and gastrointestinal absorption, undergoes rapid enzymatic conversion on passage through the liver, resulting in an estimated 75% of the dose entering the systemic circulation [58]. After administration of oral oseltamivir, the area under the plasma concentration versus time curve (AUC) increases proportionately with dose over the range 20 mg to 1 g. Peak plasma concentrations are achieved between 2.5 hr and 6 hr after administration and the terminal plasma elimination half-life is between 6.8 hr and 9.3 hr. Oseltamivir is systemically distributed and maintains therapeutic concentrations in lung tissue at 24 hr post-dose: the elimination half-life in bronchoalveolar lavage ﬂuid is fourfold longer than in plasma [59]. There is little penetration into the central nervous system. The pharmacokinetics (both absorption and elimination) of oseltamivir are similar in young and in healthy elderly volunteers. Reductions in the dose are recommended for individuals with a creatinine clearance of less than 30 mL/min. As for zanamivir, the antiviral activity, clinical eﬃcacy, and tolerability of oseltamivir have been evaluated in double-blind, placebo-controlled studies of experimental inﬂuenza A (H1N1) infection. In one such study, oseltamivir was assessed for both treatment and prevention of experimentally induced inﬂuenza [60]. In the treatment study, various dosages (20, 100, or 200

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mg twice daily or 200 mg once daily for 5 days) of oral oseltamivir were initiated 28 hr after experimental infection. All dosages signiﬁcantly reduced the titre and duration of virus shedding in nasal washes and signiﬁcantly reduced the severity and duration of clinical symptoms. In naturally acquired infection, oseltamivir reduced duration of illness by 1 to 11⁄2 days [61,62], with a suggestion that secondary complications such as bronchitis and sinusitis were also reduced [61]. Oseltamivir is associated with nausea and vomiting in about 10% of those treated but the incidence of gastrointestinal side eﬀects is reduced (without altering the pharmacokinetics) by taking the drug with food. Oseltamivir, in a dose of 75 mg once daily, was 50% eﬀective in the prevention of inﬂuenza and 84% eﬀective in the prevention of illness when given as prophylaxis during a community epidemic [63]. In the family setting, the same dose of oseltamivir prevented inﬂuenza in 89% of families when it was given to exposed family members 12 years of age or older [64]. Mutations in the neuraminidase gene resulting in resistance to oseltamivir were detected in about 1.5% (higher in children) of individuals treated with oseltamivir [26].

USE OF ANTIVIRAL AGENTS FOR TREATMENT OF INFLUENZA When to Use The pathogenesis of inﬂuenza, with virus replication present for 24–48 hr before symptom onset and reaching a peak within 48 hr, suggests that antiviral treatment would work best if taken early after the onset of symptoms. Studies of antiviral treatment of inﬂuenza to date have excluded patients presenting with symptoms for more than 48 hours because of this theoretical consideration, and at present zanamivir and oseltamivir are approved for the treatment of inﬂuenza only in patients who have been symptomatic for less than 48 hr. Some studies have shown added beneﬁt for patients starting treatment within a shorter time; for example, Hayden and colleagues demonstrated that patients who received treatment with zanamivir within 30 hr of symptom onset recovered 2 days more quickly than patients receiving placebo [50]. Thus, antiviral therapy where recommended should be instituted as soon as possible. The exception to this is the patient with immunocompromise: such patients have increased and prolonged viral replication and it would seem appropriate to give antiviral therapy after a longer symptomatic period. There is no evidence that treatment courses of greater than 5 days are of any added beneﬁt, and since the risk of drug resistance increases with time, treatment should not exceed this duration, except in

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the setting of immunocompromise where longer treatment courses have been used. Choice of Antiviral Agent Of the four agents currently available for the treatment of inﬂuenza, the neuraminidase inhibitors have the advantages of activity against both A and B inﬂuenza viruses, good tolerability, and favorable resistance proﬁle. They are, however, more expensive than the adamantanes and there may be a role for amantadine or rimantadine in speciﬁc settings; for example, in an inﬂuenza A outbreak in a residential care facility, or where resistance to the neuramindase inhibitors is present. Rimantadine is preferred to amantadine because of the high incidence of neuropsychological side eﬀects with amantadine but is currently not licensed in the United Kingdom. Oseltamivir is likely to be easier to administer than zanamivir in an elderly or pediatric population. There have, however, been no direct comparisons of these agents as regards eﬃcacy and tolerability; such a study will be important for formulation of guidelines concerning inﬂuenza treatment. Patient Groups In previously ﬁt individuals, inﬂuenza causes signiﬁcant morbidity at an individual level, as well as signiﬁcant economic impact in terms of lost productivity. Treatment with antiviral agents generally reduces the period of illness by one day and expedites return to usual activities. Several studies have attempted to analyze the cost-eﬀectiveness of antiviral treatment in previously healthy individuals, oﬀsetting the personal and economic impact of illness due to inﬂuenza against the cost of drugs and health-care services required for their administration [65–69]. Their conclusions have been conﬂicting, and antiviral agents for inﬂuenza in previously healthy adults are currently not recommended except in circumstances where there would be exceptional beneﬁt from an earlier return to usual activities [26]. In the high risk patient, however, inﬂuenza is more likely to be severe and complicated and preliminary evidence suggests that early antiviral therapy has a signiﬁcant impact on duration of illness and complication rate [51]. Assuming this to be the case, cost-beneﬁt analysis of the use of antiviral treatment in high-risk patients demonstrates a beneﬁt, particularly if treatment reduces the rate of hospitalization [70,71]. Antiviral treatment for highrisk patients with illness due to inﬂuenza is recommended both in the United States and Britain, although again no recommendations can be made regarding choice of agent because of the lack of comparative studies [72,73]. Treatment should be given regardless of prior vaccination status.

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To date there is little experience of the use of antiviral drugs for inﬂuenza in patients with impaired immunity. Patients immunocompromised following bone marrow or solid organ transplantation, or because of chemotherapy or steroid use, are at increased risk of severe infection and it is not yet clear whether such patients should receive a prolonged course of antiviral therapy, with the associated risk of resistance [74]. Zanamivir was eﬀective and well tolerated in one small observational study of seven children with inﬂuenza virus infection following stem cell transplantation; patients were treated with zanamivir until virus could no longer be isolated from nasopharyngeal secretions, the median duration being 15 days (range 5–44) [75]. HIVinfected individuals may be at risk of more severe inﬂuenza if signiﬁcantly immunosuppressed, and antiviral treatment for inﬂuenza is probably indicated for those with a CD4 count of less than 200 cells/AL [76]. No interactions with antiretroviral medications have been described. Method of Diagnosis None of the anti-inﬂuenza drugs have any useful eﬃcacy against other respiratory viruses, and their use should be based on proof or strong possibility of inﬂuenza. Viral culture or serological diagnosis, although of use for surveillance and epidemiological study, are not suﬃciently rapid for the diagnosis of individual cases of inﬂuenza prior to antiviral therapy, and in recent years attention has focused on newer rapid diagnostic assays. Antigen detection tests using immunoﬂuorescence or enzyme-linked immunoassay generally have limited sensitivity (approximately 70%) but high speciﬁcity (90%) and may be of use for the exclusion of inﬂuenza [77]. Several diagnostic kits are available that may be used outside the laboratory at the point of care [78]. Detection of viral nucleic acid by reverse-transcriptase polymerase chain reaction is more sensitive (around 90%) but may be less accessible for routine use [79,80]. Such tests are costly, and there has been debate regarding their cost-eﬀectiveness compared to diagnosis on clinical grounds alone. Most treatment studies have shown that a clinical diagnosis is 60–70% accurate in an epidemic setting [50,51,61,62]; this increases to 79% if patients have high fever and cough [81,82]. The conclusion from these decision analyses is that in nonepidemic stages of the inﬂuenza cycle, cost-beneﬁt analysis favors rapid testing to conﬁrm inﬂuenza prior to antiviral therapy; in an epidemic, where the probability of a patient presenting with inﬂuenza-like symptoms having inﬂuenza exceeds 35–40%, empirical treatment on clinical grounds alone is the preferred option [83,84]. The success of this approach depends on accurate surveillance to determine inﬂuenza activity at a given time, and a cascade of information to primary care and hospital physicians when inﬂuenza is circulating [85].

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PREVENTION OF INFLUENZA Use of Antiviral Agents for Prophylaxis All of the currently available antiviral drugs for inﬂuenza have been shown to be eﬀective as prophylaxis if taken prior to or shortly after exposure. Prophylaxis has been shown to have additional beneﬁt to vaccination, in part because of poor immune response to the vaccine, particularly in the elderly or immunosuppressed, or because of poor antigenic match between infecting and vaccine strains. Thus prophylaxis should be given where indicated regardless of vaccination history. Daily amantadine or rimantadine reduce infection rates by 50–80% during inﬂuenza A outbreaks, although again there is concern about the emergence and transmission of resistant virus [35,86]. Rimantadine is preferable to amantadine because of its side-eﬀect proﬁle. As described earlier, both zanamivir (at a dose of 10 mg daily by inhalation) and oseltamivir (75 mg daily or twice daily orally) have been shown to be protective against natural and experimental inﬂuenza infection [54,55,63,64], although zanamivir is currently not licensed for prophylactic use. Prior to the inﬂuenza season, prophylaxis should be considered for individuals at high risk for severe and complicated inﬂuenza who have not been vaccinated or who have been vaccinated too recently for a protective immune response to develop. In an outbreak, residents and staﬀ of residential care homes (whether vaccinated or not), and indeed household contacts of conﬁrmed cases, beneﬁt from prophylaxis [55,87]. In an outbreak situation, prophylaxis should be given for 14 days, or until 7 days have elapsed since the onset of the last conﬁrmed case of inﬂuenza [88]. Other measures to reduce spread of infection include restricting visitors, instructing staﬀ of hospitals or residential care homes to stay away if unwell, and respiratory isolation of ill patients [89]. Vaccination In preventive terms, annual vaccination of high-risk individuals is the single most important and cost-eﬀective intervention in the prevention of inﬂuenza [90–92]. Vaccination of staﬀ caring for high-risk patients in hospitals or residential homes has also been shown to reduce mortality in their patients [93,94]. Current inﬂuenza vaccines are inactivated trivalent vaccines containing two inﬂuenza A subtypes (H1N1 and H3N2) and one inﬂuenza B subtype. Vaccine eﬃcacy is high in healthy school-age children and adults, but reduced in infants, the elderly, and immunosuppressed persons [95–99]. To provide continuing protection, annual vaccination is necessary and vaccine is prepared each year using viral strains similar to those predicted to be circulating the forthcoming winter. Vaccination is generally well tolerated, with occa-

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sional local inﬂammation at the injection site, and rarely short-lived febrile symptoms [100,101]. An association with Guillain-Barre´ syndrome has been reported, but the risk is extremely low [102]. Egg hypersensitivity is the only absolute contraindication (since the vaccine virus is grown in eggs prior to inactivation), but the vaccine is not recommended in pregnancy. Young children and elderly and immunosuppressed individuals respond relatively poorly to the inactivated vaccine, and in recent years, there has been interest in the development of a live attenuated vaccine for inﬂuenza. This would have the advantages of high antigenic load at the site of inﬂuenza infection—that is, the nasopharynx—and the possibility of a broader, more physiological immune response, including local IgA production as well as systemic antibody responses to a wider range of antigens [103,104]. Several studies have examined the protective eﬃcacy of live vaccines and in general found comparable or improved eﬃcacy compared to inactivated vaccines, including in children and high-risk patients [105–108]. One randomized placebo-controlled, double-blind study in nursing home residents compared live attenuated vaccine plus inactivated vaccine with inactivated vaccine alone, and found signiﬁcantly lower rates of infection in those individuals who received both vaccines [109]. Future developments in inﬂuenza vaccines are likely to include the production of vaccine viruses using cell culture systems rather than eggs, the use of subunit or nucleic acid vaccines, and the development of adjuvants and delivery systems that may allow longerlived immunity. Inﬂuenza vaccine is currently recommended for all individuals at risk for severe and complicated inﬂuenza—that is, those individuals for whom antiviral treatment is recommended [110]. Despite this, uptake is generally poor. There are economic and social arguments for extending vaccination coverage to include healthy adults and school-age children [92]. CONCLUSIONS The inﬂuenza virus is likely to coexist with the human race for the foreseeable future, and although we have made great advances in our understanding of viral pathogenesis and epidemiology, there is much work still to be done. The recent development of the neuraminidase inhibitors is an exciting advance, and novel diagnostic methods may also help in diagnosis of individual cases and study of the virus at a population level. However, there remain many unresolved issues. First, while the evidence to date suggests that all groups of patients beneﬁt from antiviral therapy if administered early in their illness, the cost-eﬀectiveness of such treatment has not been established in all groups. More research is required, particularly in patients at high risk for severe and complicated inﬂuenza, as well as other groups such as pregnant women,

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infants, and the immunosuppressed. A direct comparison between agents is required in order to formulate evidence-based guidelines recommending particular agents, and the possible beneﬁts of multiple drug regimens explored. The issue of diagnostic testing as opposed to a clinical diagnosis needs to be clariﬁed. As our experience with these antiviral agents grows, it will be important to be vigilant for development of resistance both locally and globally. When considering treatment of inﬂuenza virus infections, it is important to consider the wider picture. Treatment of established inﬂuenza infection is a small part of this picture in terms of the control of inﬂuenza both locally and globally, the mainstay of prevention being annual vaccination using viral strains predicted to be circulating in the coming year. In costbeneﬁt terms, vaccination has a much greater (and additional) impact than antiviral treatment of ill patients, and it is important that vaccination remains the priority in any control strategy for inﬂuenza. Similarly, the use of antiviral agents for prophylaxis is an important element in control of infection in close contacts of cases, whether in a household or hospital. In conclusion, the recent development of new agents and assays for inﬂuenza infection oﬀers the potential for improved control over inﬂuenza in individuals and populations. It is to be hoped that our expanding knowledge of this infection will eventually allow us to control or inﬂuence the pandemics that have caused so much mortality and morbidity over past centuries.

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18 Severe Acute Respiratory Syndrome Thomas M. File, Jr. Northeastern Ohio Universities College of Medicine, Rootstown and Summa Health System Akron, Ohio, U.S.A.

INTRODUCTION From late February through mid-March 2003, public health oﬃcials from several countries worldwide had identiﬁed a newly described atypical respiratory illness, which was termed severe acute respiratory syndrome (SARS). This was ﬁrst recognized in Guandong Province in southeast China in late 2002 and subsequently spread globally during March and April 2003. This newly described infectious disease appears to be highly contagious by close contact and has been associated with signiﬁcant morbidity and mortality. Within a matter of weeks after the World Health Organization (WHO) issued its global health alert on March 15, 2003, an unprecedented amount of information has become known about this disease. This has in part been due to a coordinated eﬀort of several international organizations, but most notably the World Health Organization (WHO) and the Centers for Disease Control and Prevention (CDC). 365

366

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SARS—DEFINITION As determined by a consensus of worldwide public health oﬃcials in March 2003, surveillance case deﬁnitions for SARS included both ‘‘suspect’’ and ‘‘probable’’ cases [1,2]. A suspect case includes a respiratory illness of unknown etiology with onset since February 1, 2003, and with the following criteria: (1) measured temperature higher than 100.4jF (>38.0jC); (2) one or more clinical ﬁndings of respiratory illness (e.g., cough, shortness of breath, diﬃculty breathing, hypoxic, or radiographic ﬁndings of either pneumonia or acute respiratory distress syndrome); (3) travel within 10 days of onset of symptoms to an area with suspected or documented community transmission of SARS (excluding areas with secondary cases limited to health care workers or direct household contacts or close contact within 10 days of onset of symptoms with either a person with a respiratory illness and travel to a SARS area or a person under investigation or suspected of having SARS). A probable case is deﬁned as a suspect case with either radiographic evidence of pneumonia or respiratory distress syndrome or autopsy ﬁndings consistent with respiratory distress syndrome without an identiﬁable cause. On April 29, 2003, the CDC’s interim surveillance case deﬁnition for SARS had been updated to include laboratory criteria for evidence of infection with the SARS-associated coronavirus (see etiology), (Table 1) [2]. Although at the time of this writing no instances of SARS-associated coronavirus had been detected in persons who were asymptomatic, there remained the possibility of subclinical infection; and in such cases, laboratory detection might be able to identify patients with mild respiratory illness or those who are asymptomatic (Fig. 1).

EPIDEMIOLOGY As of the end of April 2003, over 5500 cases of suspect or probable SARS had been identiﬁed in approximately 26 countries [3]. The syndrome was observed primarily in adults ages 25 through 70, and children have been relatively spared. There appears to be no signiﬁcant underlying predisposing condition to the development of SARS; however, the elderly and patients with underlying conditions are at greater risk of dying. Earlier in the evaluation of this syndrome most of the descriptions were of patients who required hospitalization. However, as more cases have been identiﬁed, particularly in the Western countries, it has become apparent that many patients have not required hospitalization. SARS appears to be transmitted by close contact, most probably via direct contact with respiratory secretions [4,5]. The majority of early cases

SARS

367

TABLE 1 Updated U.S. Surveillance Case Deﬁnition for Severe Acute Respiratory Syndrome (SARS)—April 29, 2003 Clinical criteria Asymptomatic or mild respiratory illness Moderate respiratory illness Temperature of >100.4jF (>38jC), and One or more clinical findings of respiratory illness (such as cough, shortness of breath) Severe respiratory illness Same as for moderate, plus Radiographic evidence of pneumonia, or Respiratory distress syndrome, or Autopsy findings consistent with pneumonia or respiratory distress syndrome without an identifiable cause Epidemiological criteria Travel within 10 days of onset of symptoms to an area with current or recently documented or suspected community transmission of SARS (China, Hong Kong, Singapore, Taiwan, Toronto, Hanoi) Close contact within 10 days of onset of symptoms with a person known or suspected to have SARS infection. Close contact is defined as having cared for or lived with a person known to have SARS or having a high likelihood of direct contact with respiratory secretions and/or body fluids of a patient known to have SARS. Examples include kissing or embracing, sharing eating or drinking utensils, close conversation (<3 feet), physical examination, and any other direct contact between persons. Close contact does not include activities such as walking by a person or sitting across a waiting room or office for a brief period of time. Laboratory criteria Confirmed Detection of antibody to SARS-CoV in specimens obtained during acute illness or > 21 days after illness onset, or Detection of SARS-CoV RNA by RT-PCR confirmed by a second PCR assay, by using a second specimen Isolation of SARS-CoV Negative Absence of antibody to SARS-CoV in convalescent serum obtained > 21 days after symptom onset Undetermined: laboratory testing either not performed or incomplete Case classificationa Probable case: meets the clinical criteria for severe respiratory illness of unknown etiology with onset since February 2003, and epidemiological criteria; laboratory criteria confirmed, negative, or undetermined Suspect case: meets the clinical criteria for moderate respiratory illness of unknown etiology with onset since February 2003, and epidemiologic criteria; laboratory criteria as for probable case a

Asymptomatic SARS CoV infection or clinical manifestations other than respiratory illness might be identified as more is learned about SARS-CoV infection. Source: Ref. 2.

368

FIGURE 1 Checklist for evaluation of patient with possible SARS.

File

SARS

369

have been reported among health care workers and family members of aﬀected persons. However, evidence of community spread of the disease is emerging, suggesting that other modes of transmission, such as airborne or direct contact, may also have a role. Clusters of cases in community settings such as hotels and apartment buildings demonstrate that transmission can be eﬃcient. Many household contacts have become ill. Early epidemiological evidence indicates that the transmission of SARS is facilitated by face-to-face contact, and this still appears to be the most common mode of spread. However, airborne transmission may have a role in some settings, and it could account for extensive spread within buildings and other conﬁned areas that has been observed in some places in Asia. ETIOLOGY Several diﬀerent laboratories have identiﬁed a novel coronavirus in Vero E6 cell cultures inoculated with respiratory secretions and lung tissue of infected patients [6,7]. Other techniques, including electron microscopy, RT-PCR, and serovonversion, have also pointed to this as the causative agent. The sequence of the viral genome has been determined: it indicates no close relationship with any of the known human or animal coronaviruses. Although there is speculation the virus originated in animals, at the time of this report, the source of the virus is undetermined. Of the 50 patients with clinical SARS described by Peiris et al. 45 had serological or PCR evidence of SARS-associated coronavirus infection; and of the ﬁve cases which were unconﬁrmed, four had serological testing prior to 14 days of onset of illness (possibly prior to the time of seroconversion—see Diagnosis, below) [8]. CLINICAL MANIFESTATIONS The initial descriptions of the clinical manifestations of SARS have come from reports of patients who have required hospitalization [9–11]. In such patients the disease is often reported as a biphasic illness: an initial acute febrile phase followed by a lower respiratory illness phase. At the time of this writing, the mortality of probable SARS cases is 217/3816 (5.6%). It is possible, as more data become available from sero-epidemiological studies, that a milder form of the infection (including subclinical infection) will emerge. The illness generally begins with a prodrome of fever, often associated with chills, rigors, and myalgia. Headache and severe malaise may accompany this phase. Rash and gastrointestinal symptoms have been absent in most cases, although in one outbreak within an apartment complex in Hong Kong, diarrhea was found in 66% of cases. After a typical period of 3–7 days, a lower

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respiratory phase may begin with the onset of nonproductive cough and progressive pneumonia. In the initial reports of cases, 10–20% of patients required intensive care unit management and mechanical ventilation. The presenting symptoms of patients admitted to the hospital for SARS from three published series is presented in Table 2 [8,10,12]. Most patients were admitted to the hospital several days after the onset of symptoms. The most common initial complaints were fever and chills or rigors. Upper respiratory tract symptoms such as rhinorrhea and sore throat were present in a minority of patients. At the time of examination, abnormal auscultatory ﬁndings were present in 19 (38%) [8]. Chest x-ray ﬁnding abnormalities are usually absent during the initial phase of illness, but ﬁndings become progressively abnormal during the lower respiratory illness phase. Initially this is characterized by early focal interstitial inﬁltrates progressing to more generalized inﬁltrates. ARDS has occurred in many patients who become very seriously ill. Laboratory abnormalities most often associated with SARS include absolute lymphopenia, mild neutropenia, and thrombocytopenia. Mild to moderately elevated creatine phosphokinase, lactate dehydrogenase, and transaminase levels were seen in 30–80% of cases (Table 3). Lee et al. found that advanced age, male sex, a high peak creatine phosphokinase value, a high lactate dehydrogenase level, a high initial neutrophil count (i.e., 4.6 vs. 3.7109/L), and a low serum sodium level were signiﬁcant predictive factors for ICU admission and death [12]. On multivariate analysis, the only factors that were predictive of an adverse outcome were advanced age, a high peak lactate dehydrogenase level, and a higher absolute neutrophil count.

TABLE 2

Symptoms of Patients with SARS at Presentation (%)

Symptoms

Peirisa (50)

Leeb (138)

Poutanenc (10)

Fever Chills Cough Myalgia Rhinorrhea Diarrhea Headache

100 74 62 54 24 10 20

100 73 57 61 23 20 56

100 — 100 20 — 50 30

( )=number of patients. a Ref. 8. b Ref. 12. c Ref. 10.

SARS

TABLE 3

371 Laboratory Abnormalities on Presentation of Patients with

SARS (%) Laboratory test Lymphopenia Thrombocytopenia Elevated CPK Elevated LDH Elevated transaminases

Pierisa

Leeb

Poutanenc

68 40 26 — 34

70 45 32 71 23

89 33 56 80 78

The percentage is based on the number of patients who had the test performed. CPK=creatine phosphokinase. LDH=lactate dehydrogenase. a Ref. 8. b Ref. 12. c Ref. 10.

Characteristics of the initial patients reported to the CDC with either suspect or probable SARS in the United States are shown in Table 4. As of the end of April 2003, the overall worldwide mortality rate of probable cases was 6.5%; however, at that time there had been no reported deaths in the United States. DIAGNOSIS At the time of this writing, there were no speciﬁc diagnostic tests available in general laboratories for the novel coronavirus strain. However, several laboratories, including the CDC and WHO, were working to develop a variety of methods, including PCR-based and serological tests. Information from a limited number of samples tested for serology suggests that antibodies may not be detectable by ELISA or indirect ﬂuorescence until a couple of weeks after the onset of symptoms [6]. TREATMENT At the time of this writing, there is no speciﬁc therapy recommended. A variety of treatments have been attempted, but there are no controlled data. Most patients have been treated throughout the illness with broad-spectrum antimicrobials, supplemental oxygen, I.V. ﬂuids, and other supportive measures. Some clinicians have advocated a combination of ribaviran and corticosteroids, but the eﬃcacy of these drugs has not been established. Early testing of ribaviran and other antiviral compounds against the novel coronavirus had not produced evidence of in vitro activity [13].

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TABLE 4 Characteristics of SARS Cases in the United States (as of April 29, 2003)

Characteristic Age 0–4 5–17 18–64 z65 Unknown Sex Female Male Unknown Race White Black Asian Unknown Exposure Travela Close contact HCWb Hospitalized >24 hr Yes No Unknown Required ventilator Yes No Unknown Deaths SARS-assoc coronavirus findings Confirmed Negative Undeterminedc a

Probable cases

Suspect cases

(N=56)

(n=233)

No. (%)

No.(%)

7 (13) 3 (5) 33 (59) 12 (21) 1 (2)

36 14 159 21 3

(15) (6) (68) (9) (2)

24 (43) 30 (54) 2 (4)

115 (49) 117 (50) 1 (0)

26 (46) 0 (0) 25 (45) 4 (7)

131 5 83 14

54 (96) 1 (2) 1 (2)

213 (91) 16 (7) 4 (2)

37 (66) 18 (32) 1 (2)

9 (22) 178 (76) 4 (2)

2 (4) 53 (95) 1 (2) 0 (0)

1 228 4 0

6 (11) 13 (23) 37 (66)

0 (0) 41 (18) 192 (82)

(56) (2) (36) (6)

(0) (98) (2) (0)

to Mainland China, Hong Kong, Hanoi, Singapore, Toronto. Health care worker. c Collection and/or laboratory testing has not been completed. Source: CDC. Updated interim U.S. cases. Available at http://www.cdc.gov/ ncidod/sars/casedeﬁnition.htm. b

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373

PREVENTION Because the causative agent of SARS is contagious, prevention measures center on avoidance of exposure and infection control strategies for suspected cases and contacts. Guidelines for infection control have been published and should be consulted for updated recommendation [14]. Health care workers encountering a possible case of SARS (suspected or probable) should take meticulous safety precautions and should seek advice from an expert in SARS infection control. Hospitalized patients with suspected SARS should be isolated in negative pressure rooms; health care workers should wear masks (N95 respirator such as used for tuberculosis) to prevent air-droplet and airborne acquisition. Because coronaviruses can survive on environmental surfaces, good hand washing is highly recommended as well. Figure 2 represents a checklist used at our hospital to evaluate patients for the possibility of SARS. SUMMARY Because a new virus causes SARS, it is very diﬃcult to predict the eventual signiﬁcance of this infection. However, at the time of this writing, there is great concern about its future impact. It has had enormous economic and political impact on the aﬀected areas of the world. Although signiﬁcant progress has been made concerning the etiology, epidemiology, and prevention of this virus, many important questions remain: Why do some people develop severe illness and others have only mild symptoms? Is there a large segment of infected patients with subclinical infection? How long do patients shed the virus? Will there be speciﬁc antiviral therapy? Will a vaccine be eﬀective? Without answers to some of these questions, the eventual outcome of SARS remains unclear. REFERENCES 1. WHO. Case deﬁnitions for surveillance of severe acute respiratory syndrome SARS). http:/www.who.int/csr/sars/casedeﬁnition/htm 2. CDC. Updated interim U.S. case deﬁnition of severe acute respiratory syndrome (SARS). http:/www.cdc.gov/ncidod/sars/casedeﬁnition/htm 3. WHO. Cumulative Number of Reported Probable Cases of Severe Acute Respiratory Syndrome (SARS). Vol. 2003. WHO, 2003. 4. Outbreak of severe acute respiratory syndrome—Worldwide, 2003. JAMA 2003; 289:1775–1776. 5. Update: Outbreak of severe acute respiratory syndrome—worldwide, 2003. MMWR Morb Mortal Wkly Rep 2003; 52:241–246, 248. 6. Ksiazek TG, Erdman D, Goldsmith C, et al. A novel coronavirus associated with severe acute respiratory syndrome. N Engl J Med 2003; 10:10.

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7. Drosten C, Gunther S, Preiser W, et al. Identiﬁcation of a novel coronavirus in patients with severe acute respiratory syndrome. N Engl J Med 2003; 10:10. 8. Peiris JSM, Lai ST, Poon LLM, Yam LYC, et al. Coronavirus as a possible cause of severe acute respiratory syndrome. Lancet 2003. Published online April 8, 2003. http:/image.thelancet.com/extras/033477web.pdf. 9. Tsang KW, Ho PL, Ooi GC, et al. A cluster of cases of severe acute respiratory syndrome in Hong Kong. N Engl J Med 2003; 11:11. 10. Poutanen SM, Low DE, Henry B, et al. Identiﬁcation of severe acute respiratory syndrome in Canada. N Engl J Med 2003; 10:10. 11. Preliminary clinical description of severe acute respiratory syndrome. Morb Mortal Wkly Rep 2003; 52:255–256. 12. Lee N, Hui D, Wu A, Chan P, Cameron P, et al. A major outbreak of severe acute respiratory syndrome in Hong Kong. N Engl J Med 2003. Published at www.nejm.org on April 7, 2003. 13. CDC. Severe acute respiratory syndrome (SARS) and coronavirus testing— United States, 2003. Morb Mortal Weekly Rep 2003; 53:297–302. 14. Outbreak of severe acute respiratory syndrome—worldwide, 2003. MMWR Morb Mortal Wkly Rep 2003; 52:226–228.

Index

AAO-HNS Task Force for Rhinosinusitis, 156 Acute adult rhinosinusitis, 169 Acute bacterial maxillary sinusitis, quinolones for, 113–115 Acute bronchitis, characteristics of, 14 Acute community-acquired rhinosinusitis, 155–179 clinical manifestations, 162–170 acute adult rhinosinusitis, 169 chronic adult rhinosinusitis, 170 culture technique, 167 diagnostic modulation, 164–167 recurrent adult rhinosinusitis, 169 subacute adult rhinosinusitis, 169 temporal aspects, 169 complications, 170–171 epidemiology, 157 etiology, 157–158 management, 171–176 ancillary management, 174–175 antimicrobial management, 171– 174 role of surgery, 175–176 pathogenesis, 159–162 normal anatomy and physiology, 158–162

[Acute community-acquired rhinosinusitis] vicious cycle of respiratory infections, 162 prevention, 176 Acute exacerbations of asthma, viral respiratory tract infections and, 324 Acute exacerbations of chronic bronchitis (AECB), 43–44 penicillins and cephalosporins for, 135 quinolones for, 113 telithromycin for, 85–86 treatment cost, 7 Acute exacerbations of chronic obstructive pulmonary disease (AECOPD), 215–254 bronchodialator therapy, 240–241 characteristics of the ‘‘ideal’ antibiotic for treatment, 231–233 clinical parameters for stratifying patients into risk groups, 229–231 end point for treatment, 225–229 epidemiology, 216–219 etiology, 219–223 375

376 [Acute exacerbations of chronic obstructive pulmonary disease (AECOPD)] diagnostic procedures, 223 pathogenesis, 221–223 individual antibiotic agents, 233–240 cephalosporins, 234 ﬂuoroquinolones, 237–240 macrolides, 235–237 penicillins, 233–234 tetracycline, 235 trimethoprim-sulfamethoxazole, 234–235 mucus-clearing strategies, 243–244 prevention, 244–245 treatment with antibiotics, 223–228 treatment with corticosteroids, 241–243 Acute maxillary sinusitis (AMS): penicillins and cephalosporins for, 135–136 telithromycin for, 86–87 Acute otitis media (AOM), 3, 11–12, 44 agents commonly used in treatment of, 185 diagnosis of, 182 pathogens implicated in, 183 viral respiratory tract infections and, 324 Acute pharyngitis, 201–214 ancillary management and prevention, 210–211 antimicrobial therapy, 206–210 clinical manifestations, 203–205 etiology and epidemiology, 201–203 laboratory diagnosis, 205 management, 205–206 pathogenesis, 203 Acylovir, 8 Adamantanes, 346–348 Adenoviruses as major cause of acute bronchitis, 323 Adverse eﬀects of penicillins and cephalosporins, 132–133 Amantadine, 8, 346–348

Index Ambulatory care for patients with CAP, 258–263 American Academy of Otolarynology= Head and Neck Surgery (AAO-HNS), 156 American Thoracic Society (ATS) guidelines: for antimicrobial therapy in adults, 271 for CAP therapy, 32, 35–37, 267 appropriate use of antibiotics, 70– 71 h-lactam, 136–137 macrolides, 66–68 for risk factors of infection with DRSP, 299 Amoxicillin, for acute otitis media, 184, 187, 188, 189, 190 Ampicillin, 8 Anaerobic bacteria, 307 Anaerobic pleuropulmonary infection, 307–319 actinomycosis, 310 ancillary management, 317 antimicrobial treatment, 312–316 carbapenems, 316 ketolides, 315 new antimicrobial agents, 313–314 new ﬂuoroquinolones, 314–315 older antimicrobial agents, 312– 313 oxazolidinones, 315 clinical presentation, 310–311 diagnosis, 311–312 empyema, 310 microbiology, 309–310 pathogenesis, 308–309 prevention, 316–317 Ancillary therapy: for acute community-acquired rhinosinusitis, 174–175 for anaerobic pleuropulmonary infection, 317 for the common cold and viral bronchitis, 331–333

Index [Ancillary therapy] alternative therapies, 332 antibiotics, 332 prevention, 333 symptomatic therapies, 331–332 Anterior rhinoscopy in diagnosis of acute community-acquired rhinosinusitis, 164–165 Antibacterial activity of telithromycin, 80–83 Antibiotics, see Cost considerations in the use of antibiotics Antigenic shift, the inﬂuenza virus and, 342–343 Anti-inﬂuenza agents available in the U.S. and Europe, 346–351 Antimicrobial therapy: for acute community-acquired rhinosinusitis, 171–174 for CRTIs, 7–23 challenge of diﬀerentiating viral from bacterial RTI, 10–14 challenge of identifying causative pathogens, 9–10 challenge of resistance, 14–17 commonly used antivirals, 7, 8 educational strategies to promote rational antibiotic use, 21–23 principles of appropriate antimicrobial use, 17–20 value of guidelines, 21, 22 Antiviral therapy: for the common cold and viral bronchitis, 326–331 capsid-inhibiting compounds, 327–330 enviroxime-related compounds, 330 interferon, 326–327 soluble ICAM, 331 3-C protease inhibitors, 331 for inﬂuenza, 346–351 adamantanes, 346–348 choice of agents, 351–352 method of diagnosis, 353

377 [Antiviral therapy] neuraminidase inhibitors, 347, 348 oseltamivir, 347, 350–351 patient groups, 352–353 when to use, 351 zanamivir, 347, 348–350 Area under the serum concentrationtime curve (AUC), 38 Atypical pathogens for CAP, 285–286 AUC-MIC ratio, 38–39 for macrolides, 60 Azithromycin, 60 for CAP, 294 for once-daily dosing for CRTIs, 49 pharmacokinetic proﬁle of, 236 Bacteremic pneumococcal pneumonia, macrolide failures associated with, 65–66 Bacterial resistance to the macrolides, 62–64 Bacterial rhinosinusitis, symptoms associated with, 12 Bacterial respiratory tract infection (RTI), diﬀerentiating viral RTI from, 10–14 Blood cultures as diagnostic testing for CAP, 293 British Thoracic Society guidelines: for antimicrobial therapy in adults, 271 for establishing severity of pneumonia, 261 Bronchitis, see also Common cold and viral bronchitis Bronchodilator drugs for AECOPD, 240–241 C. pneumoniae, CAP and, 286 Canadian Infectious Disease Society, 32 Canadian Thoracic Society (CTS) guidelines: for antimicrobial therapy in adults, 270 for CAP therapy, 32

378 Capsid-inhibiting compounds for the common cold and viral bronchitis, 327–330 Carbapenems for anaerobic pleuropulmonary infection, 313–314, 316 Cardiotoxicity, quinolones therapy and, 110 Cefaclor, 184 Cefdinir, 190 Ceﬁxime: for acute otitis media, 184 once-daily dosing for CRTIs, 49 Cefpodoxime for acute otitis media, 184, 190 Cefprozil for acute otitis media, 184, 190 Ceftibuten: for acute otitis media, 184 once-daily dosing for CRTIs, 49 Ceftriaxone: for acute otitis media, 184, 188, 189, 190 once-daily dosing for, 49 Cefuroxime for acute otitis media, 184, 188, 189 Centers for Disease Control and Prevention (CDC) guidelines: for antimicrobial therapy in adults, 270 for CAP therapy, 32, 34–35 appropriate use of antibiotics, 70– 71 h-lactam, 68–71, 136 macrolides, 66–68 case deﬁnition for SARS (April 29, 2003), 366, 368 Central nervous system, quinolones and, 109–110 Cephalosporins: for AECOPD, 234 for acute otitis media, 191 for acute pharyngitis, 206 See also Penicillins and cephalosporins

Index Checklist for evaluation of patient with possible SARS, 367 Chest radiograph as diagnostic testing for CAP, 293 Chlamydia psittaci (psittacosis), 262 Chloramphenicol for anaerobic pleuropulmonary infection, 312 Chronic adult rhinosinusitis, 170 Chronic bronchitis: cost of treatment, 4, 5, 6 prevalence of, by age, in the U.S. (1970–1996), 217 trimethoprim-sulfamethoxazole for, 148–149 Chronic obstructive pulmonary disease (COPD), 3 cost of treatment, 7 deaths due to, in the U.S. (1998), 217, 218 viral respiratory tract infections and, 325 See also AECOPD Chronic rhinosinusitis, 157 Ciproﬂoxacin, 96 activity against common respiratory pathogens, 238 for CAP, 296 clinical use of, 111–112 FDA-approved dosing regimens for, 114 Clarithromycin, 60–61 once-daily dosing in treatment of CRTIs, 49 pharmacokinetic proﬁle of, 236 Clavulanate, 8 Clindamycin, 8, 147–148 for anaerobic pleuropulmonary infection, 312–313 Clinical practice guidelines for antimicrobial therapy, 21, 22 Common cold and viral bronchitis, 321–340 clinical manifestations, 325 diagnostic management, 325

Index [Common cold and viral bronchitis] etiology and epidemiology, 322 management, 325–333 ancillary management, 331–333 antivirals, 326–331 pathogenesis, 322–325 Community-acquired pneumonia (CAP), 3–6, 43–44 characteristics of, 14 cost of treatment, 7 decision tree analysis for alternative treatments of, 46 drug-resistant S. pneumoniae (DRSP) and, 15–16 linezolid for, 149–150 mortality of, 6 penicillins and cephalosporins for, 136–138 quinolones for, 112–113 telithromycin for, 85 treatment of, 31–42 vancomycin for, 149 See also Hospitalized patients with community-acquired pneumonia; Macrolides in the treatment of CAP Community-acquired pneumonia (CAP) in non-hospitalized patients, 255–278 clinical manifestations, 257–258 deﬁning low-risk patients for ambulatory care, 258–262 epidemiology, 256 etiology, 262–267 management, 269–275 length and route of antimicrobial treatment, 274–275 new drugs, 274 recommendations from recent guidelines for empirical therapy, 273–274 microbiological diagnosis, 267–269 pathogenesis of CAP, 256–257 prevention of CAP, 275

379 Computed tomography (CT): in diagnosis of acute communityacquired rhinosinusitis, 166–167, 170 in diagnostic testing for CAP, 293 Corticosteroids for AECOPD, 241–243 Cost considerations in the use of antibiotics, 43–58 methods of reducing costs in health care setting, 45 patient compliance, 45–54 combination versus monotherapy, 45–47 once-daily dosing and shortduration therapy, 48–50 pharmacoeconomics of clinical pathways, 53–54 transitional therapy, 50–53 Cost of respiratory tract infections (RTIs), 4–5, 6–7 Cough, as clinical hallmark of the common cold and acute bronchitis, 323 Coxiella burnetii (Q fever), 262 Dalfopristin, eﬀective therapy against DRSP, 274 Decision tree analysis for alternative treatments of CAP, 46 Dirithromycin, pharmacokinetic proﬁle of, 236 Doxycyclines, 146–147 Drug-resistant S. pneumoniae (DRSP), 15–16 management of CAP and, 269, 299–300 Educational strategies to promote rational antibiotic use, 21–23 Emphysema, prevalence of, by age, in the U.S. (1970–1996), 217 Empyema, 310 Enteroviruses (Evs) as major cause of the common cold, 323 Enviroxime-related compounds, 330

380 Enzymatic degradation of h-lactam, 123 Epithelial lining ﬂuid (ELF), concentration of macrolides in, 60–61 Ertapenem, 316 once-daily dosing in treatment of CRTIs, 49 Erythromycin, 59, 60 for acute otitis media, 191 for acute pharyngitis, 206–207 pharmacokinetic proﬁle of, 236 Expectorants, AECOPD and, 243–244 Facultative anaerobes, 307 Famciclovir, 8 Fluoroquinolones, 8 for AECOPD, 237–240 for anaerobic pleuropulmonary infection, 313–314 eﬀective against DRSP, 274 macrolides versus, as empiric management of outpatient CAP, 69–70 popularity of, for RTIs therapy, 37 Francisella tularensis (tularemia), 262 Gatiﬂoxacin, 37, 96, 313, 314 activity against common respiratory pathogens, 238 for CAP therapy, 295, 296 clinical use of, 112 FDA-approved dosing regimens of, 114 once-daily dosing for CRTIs, 49 Gemiﬂoxacin, 313, 314 Genotoxicity, quinolones therapy and, 110 Gram negative bacteria as cause of CAP, 286–287 Group A beta hemolytic streptococcus (GABHS), 201–203, 205–206, 210 eradication of, 206–207 Guidelines for the treatment of CAP, 32, 33–34

Index [Guidelines for the treatment of CAP] ATS guidelines, 32, 35–37, 267 CDC guideline, 32, 34–35 IDSA guideline, 32, 35, 267–268 Health-care expenditures attributed to acute/chronic rhinosinusitis in the U.S. (1996), 155 Hospitalized patients with communityacquired pneumonia, 279–306 assessment of severity of illness, 289–292 hospitalization decision, 289–291 need for ICU care, 291–292 clinical features of CAP, 280–284 diagnostic testing, 292–294 etiologic pathogens, 284–289 atypical pathogens, 285–286 gram-negative bacteria, 286–287 other organisms, 287–288 predicting pathogens for speciﬁc patient populations, 289 S. pneumoniae, 284–285 evaluation of response to therapy, 300–301 therapy of CAP, 294–300 ‘‘Ideal’’ antibiotic for the treatment of AECOPD, 231–233 Identifying causative pathogens of CRTIs, 9–10 Impact of CRTIs, 2–7 cost of RTIs, 4–5, 6–7 morbidity and mortality, 2–6 lower CRTIs, 3–6 upper CRTTs, 2–3 Infectious Diseases Society of America (IDSA) guidelines: for antimicrobial therapy in adults, 271 for CAP therapy, 32, 35, 267–268 appropriate use of antibiotics, 70–71 h-lactam, 136–137 macrolides, 66–68

Index [Infectious Diseases Society of America (IDSA) guidelines] for management and prevention of acute pharyngitis, 210 for risk factors of infection with DRSP, 299 Inﬂuenza: as major cause of acute bronchitis, 323 vaccination for, as AECOPD prevention measure, 244–245 Inﬂuenza-related respiratory tract infections, 341–363 prevention of inﬂuenza, 353–355 use of antiviral agents for prophylaxis, 353–354 vaccination, 354–355 use of antiviral agents for treatment of inﬂuenza, 351–353 choice of agent, 351–352 method of diagnosis, 353 patient groups, 352–353 when to use, 351 virological and clinical aspects, 342–351 antiviral agents, 346–351 clinical features, 344–345 epidemiology, 343–344 viral pathogenesis, 344 the virus, 342–343 Intensive care unit (ICU), need for, in care of CAP inpatients, 291–292 Interferon, 326–327 Intracellular adhesion molecule (ICAM), soluble, 331 Intranasal interferon, 327 Ketolides, 8, 75–94 for acute pharyngitis, 207 for anaerobic pleuropulmonary infection, 313–314, 315 eﬀective therapy against DRSP, 274

381 [Ketolides] general class aspects, 80 macrolide-ketolide structure, 76, 78 structure of, 76–80 telithromycin, 80–89 antibacterial activity, 80–83 PK/PD, 83–85 safety and tolerability, 88–89 therapeutic uses, 85–88 h-Lactam, 8 adult dosage of, in treatment of CARTIs, 134 for CAP therapy, 136 guide lines, 68–71 mechanism of action, 122–123 mechanisms of resistance, 123 PK/PD properties of, 128–132 Legionella, CAP and, 286 Levoﬂoxacin, 37, 314 activity against common respiratory pathogens, 238 for CAP, 295, 296 clinical use of, 112 FDA-approved dosing regimens of, 114 once-daily dosing for CRTIs, 49 Linezolid, 149–150, 315 eﬀective therapy against DRSP, 274 Lower RTIs, 3–6 viral respiratory tract infections and, 324–325 M. pneumoniae, CAP and, 286 Macrolide-ketolide structure, 76, 78 Macrolide-resistant S. pneumoniae (MRSP), 16–17 in vivo-in vitro paradox with, 65 Macrolides, 98 for acute otitis media, 184 for AECOPD, 235–237 for CAP, 59–74 bacterial resistance, 62–64 CAP guidelines and macrolides, 66–68

382 [Macrolides] in vivo/in vitro paradox with pneumococcal respiratory tract infections, 64–66 PK/PD relationships, 60–62 role for h-lactam monotherapy, 68–71 pharmacokinetic comparison of, 236 and their derivatives, 76, 77 Metronidazole for anaerobic pleuropulmonary infection, 312 Microaerophilic anaerobes, 307 Microbiological diagnosis of CAP, 267–268 Minimum inhibitory concentration (MIC), 38 Morbidity of CRTIs, 2–6 Mortality: of CAP, 6 of CRTIs, 2–6 Moxiﬂoxacin, 37, 96, 313, 314 activity against common respiratory pathogens, 238 for CAP therapy, 295, 296 clinical use of, 112 FDA-approved dosing regimens of, 114 once-daily dosing for CRTIs, 49 MRI scan in diagnosis of acute community-acquired rhinosinusitis, 167 Mucokinetic agents, AECOPD and, 243–244 Mucolytics, AECOPD and, 243–244 Nalidixic acid, 96 Nasal stuﬃness, 323 Nasopharyngitis, 203 National Center for Health Statistics (NCHSS), respiratory disorders in the U.S. (1996) according to, 2 Neuraminidase inhibitors, 347, 348

Index Nonpharmacologic interventions in preventing viral infections, 333 Norﬂoxacin, 96, 97 Obligate anaerobes, 307 Oral cephalosporins, 8 Orthomyxoviridae viruses, 342–343 Oseltamivir, 8, 347, 350–351 Otitis externa, 3 Otitis media (OM), 3, 11–12, 181–200 diagnosis, 182 pathogens, 182–185 treatment, 186–191 ﬁrst-line antimicrobial therapy, 186–187 less-useful agents, 190–191 other treatment options, 191–193 second-line agents, 188–190 See also Acute otitis media Otitis media with eﬀusion (OME), 11–12 diagnosis of, 182 Oxazolidinones for anaerobic pleuropulmonary infection, 313–314, 315 Oximetry for diagnostic testing of CAP, 293 Pandemics, inﬂuenza viruses as cause of, 341, 342–343 Parenteral cephalosporins, 8 Pathogens: associated with CAP, 262, 263, 287, 289 epidemiological and underlying conditions related to speciﬁc, pathogens, 265 clinical associations with speciﬁc pathogens 288, 289 Patient Outcomes Research Team (PORT), pneumonia prediction rule developed by, 259–261 Penicillin-resistant S. pneumoniae (PRSP), in vivo-in vitro paradox with, 64–65

Index Penicillins: for acute pharyngitis, 206 for AECOPD, 233–234 for anaerobic pleuropulmonary infection, 312–313 cephalosporins and, 121–143 adverse eﬀects, 132–133 antimicrobial activity, 124–128 clinical utility in treatment of CARTI, 133–138 mechanism of action, 122–123 mechanisms of resistance, 123 PK/PD properties, 128–132 structure activity relationships, 121–122 penicillin VK, 8 Pharmacokinetic/pharmodynamic (PK/PD) properties: of clindamycin, 147–148 of doxycyclines, 146 of ketolides, 76 of h-lactam, 128–132 of macrolides, 60–62 percentage of respiratory tract isolates susceptible at PK/PD breakpoint, 131 of quinolones, 98–111 of telithromycin, 83–85 of trimethoprim-sulfamethoxazole, 148 Pharyngitis, 44 penicillins and cephalosporins for, 134–135 streptococcal pharyngitis, 203–204 See also Acute pharyngitis Phototoxicity, quinolones therapy and, 109 Physical ﬁndings of pneumonia, 282 Picornaviruses as major cause of acute bronchitis, 322 Pleconaril, 329 Pneumococcal vaccination as AECOPD prevention measure, 244–245

383 Pneumonia. see Community-acquired pneumonia (CAP); Communityacquired pneumonia in nonhospitalized patients Pneumonia prediction rule (severity of index score), 259–261 Polysaccharide pneumococcal vaccine (PPV), 23, 275 Prevention of acute communityacquired rhinosinusitis, 176 Prevention of CRTIs, 23 Prevention of inﬂuenza, 353–355 use of antiviral agents for prophylaxis, 353–354 vaccination, 354–355 Probable case of SARS (deﬁnition), 368 Quinolones, 95–119 for CAP, 296 chemistry overview, 95–98 clinical uses, 111–115 appropriate uses, 115 appropriate use in CRTIs, 112–115 FDA-approved indications, 111– 112 history, 95–98 PK/PD properties, 98–111 structures of representative quinolones, 96 Quinupristin, as eﬀective therapy against DRSP, 274 Radiography in diagnosis of acute community-acquired rhinosinusitis, 166 Recurrent adult rhinosinusitis, 169 Respiratory tract infection, inﬂuenzarelated. see Inﬂuenza-related respiratory tract infection Rhinorrhea, 323 Rhinosinusitis: symptoms associated with viral and bacterial rhinosinusitis, 12 See also Acute community-acquired rhinosinusitis

384 Rhinoviruses (RVs) as major cause of the common cold, 323 Rimantadine, 8, 346–348 Risk factors for pneumonia, 257 S. pneumoniae, see Streptococcus pneumoniae SARS. see Severe acute respiratory syndrome (SARS) Serologic testing, as diagnostic testing for CAP, 293 Severe acute respiratory syndrome (SARS), 365–374 characteristics of SARS cases in the U.S. (April 29, 2003), 371 checklist for evaluation of patients with SARS, 367 clinical manifestations, 369–372 deﬁnition, 365 diagnosis, 372 epidemiology, 368–369 etiology, 369 prevention, 373 treatment, 372 U.S. surveillance case deﬁnition for SARS (April 29, 2003), 366 Sinus and Allergy Health Partnership guidelines for acute CAP, 171, 173 Sinusitis, 44 cost of treatment, 4, 5, 6 Smoking, cessation of: as AECOPD prevention measure, 244 as CAP prevention measure, 275 Sneezing, 323 Soluble ICAM, 331 Sputum culture, 293 Sputum gram stain, 293 Streptococcal pharyngitis, 203–204 Streptococcus aureus, CAP and, 287, 288 Streptococcus pneumoniae, 44 CAP and, 262, 284–285

Index [Streptococcus pneumoniae] macrolide-resistant, 16–17, 62–63 in vivo-in vitro paradox with, 65 penicillin-resistant, in vivo-in vitro paradox with, 64–65 See also Drug-resistant S. pneumoniae Subacute adult rhinosinusitis, 169 Sulbactam, 8 Surgery: for acute community-acquired rhinosinusitis, 176 for anaerobic pleuropulmonary infection, 317 Suspect case of SARS (deﬁnition), 368 Symptoms: of CAP, 280–282 of SARS, 370 Telithromycin, 76, 80–89 for acute pharyngitis, 207 antibacterial activity, 80–83 for DRSP, 274 once-daily dosing for CRTIs, 49 PK/PD properties, 83–85 safety and tolerability, 88–89 therapeutic uses, 85–88 Temporal aspects of rhinosinusitis, 169 Tetracyclines, 8, 146–147 for AECOPD, 235 3-C protease inhibitors, 331 Tonsillitis: penicillins and cephalosporins for treatment of, 134–135 telithromycin for tonsillitis pharyngitis, 88 Topical therapy for acute otitis media, 193 Toxicities associated with quinolones, 109–111 cardiotoxicity, 110

Index [Toxicities associated with quinolones] central nervous system, 109–110 genotoxicity, 110 phototoxicity, 109 severe idiosyncratic and immunemediated reactions, 110 Trimethoprim-sulfamethoxazole, 8, 148–149 for acute otitis media, 184 for AECOPD, 234–235 Trovaﬂoxacin, 96, 314 clinical use of, 112 Ultrasound in diagnosis of acute community-acquired rhinosinusitis, 165–166 United States (U.S.): characteristics of SARS cases in (April 29, 2003), 371 health-care expenditures attributed to acute/chronic rhinosinusitis in (1996), 155 surveillance case deﬁnition for SARS in (April 29, 2003), 366 Upper CRTIs, 2–3

385 Vaccines: pneumococcal vaccination as AECOPD prevention measure, 244–245 polysaccharide pneumococcal vaccine (PPV), 23, 275 for prevention of CRTIs, 23 for prevention of inﬂuenza, 354–355 Valacyclovir, 8 Vancomycin, 149 for DRSP, 274 Vicious cycle of respiratory infections, 162 Viral bronchitis, see Common Cold and viral bronchitis Viral respiratory tract infections (VRTIs), 2–3 diﬀerentiating bacterial RTI from, 10–14 Viral rhinosinusitis, symptoms associated with, 12 World Health Organization (WHO), SARS data from, 365 Zanamivir, 8, 347, 348–350

About the Editors

CHARLES H. NIGHTINGALE is Vice President for Research and Director of the Institute for International Healthcare Studies at Hartford Hospital, Connecticut, as well as Research Professor at the University of Connecticut School of Pharmacy, Storrs. The author of approximately 500 journal articles, numerous book chapters, and 238 published abstracts, Dr. Nightingale is a Fellow of the American College of Clinical Pharmacology and the Infectious Disease Society of America, as well as a member of the American Society for Clinical Pharmacology and Therapeutics, among others. An editorial board member for numerous publications, Dr. Nightingale received the B.S. degree (1961) from Fordham University, Bronx, New York, the M.S. degree (1966) from St. John’s University, Jamaica, New York, and the Ph.D. degree (1970) from the State University of New York at Buﬀalo. PAUL G. AMBROSE is Director of the Division of Infectious Diseases, Cognigen Corporation, Buﬀalo, New York, Assistant Clinical Professor of the University of the Paciﬁc School of Pharmacy, Stockton, California, as well as a member of the Buﬀalo Pharmacometrics Study Unit, State University of New York at Buﬀalo. The author or coauthor of over 50 books, book chapters, and journal articles, Dr. Ambrose serves on the editorial boards of Antimicrobial Agents and Chemotherapy, Antibiotics for Clinicians, and the Journal of Infectious Disease Pharmacotherapy. Additionally, Dr. Ambrose is a member of the Infectious Disease Society of America and the Society of Infectious Disease Pharmacists. Dr. Ambrose received the Pharm.D. degree (1992) from the University of the Paciﬁc, Stockton, California.

THOMAS M. FILE, JR. is Chief of the Infectious Disease Service and Director of HIV Research, Summa Health System, Akron, Ohio, as well as Professor of Internal Medicine and Master Teacher, Northeastern Ohio Universities College of Medicine, Rootstown, Ohio. He is the author of more than 200 articles, textbook chapters, and abstracts and is on the editorial board of the Journal of Respiratory Disease. Holding many professional society memberships, Dr. File is a Fellow of the American College of Physicians, the Infectious Diseases Society of America (IDSA), and the American College of Chest Physicians, and is a member of the American Thoracic Society. He is also on IDSA and American Thoracic Society committees for guidelines on community-acquired pneumonia. Dr. File received the B.A. degree (1968) from Albion College, Michigan, the M.D. degree (1972) from the University of Michigan Medical School, Ann Arbor, and the M.S. degree (1997) in Medical Microbiology from The Ohio State University, Columbus.